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Full text of "Marihuana and health"






94th Congress 
2d Sessio] 



gress 1 
;ion J 



COMMITTEE PRINT 



UNIV. OF R MR 



DOCUMENTS DEPT. 

MARIHUANA AND HEALTH 



9*W3 



FIFTH ANNUAL REPORT 

TO THE 

U.S. CONGRESS 

FROM THE 

SECRETARY OF HEALTH, EDUCATION, 
AND WELFARE, 1975 

PREPARED FOR THE 

SUBCOMMITTEE ON ALCOHOLISM AND NARCOTICS 

OF THE 

COMMITTEE ON LABOR AND 

PUBLIC WELFARE 

UNITED STATES SENATE 




AUGUST 1976 



ttftfis 



Printed for the use of the Committee on Labor and 
Public Welfare 






76 



U.S. GOVERNMENT PRINTING OFFICE 
WASHINGTON : 1976 



— — — 






-w-Citfi 



OS 



AUG 1 9 ]Q 76 






COMMITTEE ON LABOR AND PUBLIC WELFARE 

HARRISON A. WILLIAMS, Jr., New Jersey, Chairman 
JENNINGS RANDOLPH, West Virginia JACOB K. JAVITS, New York 

CLAIBORNE PELL, Rhode Island RICHARD S. SCHWEIKER, Pennsylvania 

EDWARD M. KENNEDY, Massachusetts ROBERT TAFT, Jr., Ohio 

GAYLORD NELSON, Wisconsin J. GLENN BEALL. Jr., Maryland 

WALTER F. MONDALE, Minnesota ROBERT T. STAFFORD, Vermont 

THOMAS F. EAGLETON, Missouri PAUL LAXALT, Nevada 

ALAN CRANSTON, California 
WILLIAM D. HATHAWAY, Maine 
JOHN A. DURKIN, New Hampshire 

Donald Elisburg, General Counsel 

Marjorib M. Whittaker, Chief Clerk 

Jay B. Cutler, Minority Counsel 



Subcommittee on Alcoholism and Narcotics 
WILLIAM D. HATHAWAY, Maine, Chairman 
JENNINGS RANDOLPH, West Virginia RICHARD S. SCHWEIKER, Pennsylvania 

HARRISON A. WILLIAMS, Jr., New Jersey JACOB K. JAVITS, New York 
EDWARD M. KENNEDY, Massachusetts J. GLENN BEALL, Jr., Maryland 
WALTER F MONDALE, Minnesota PAUL LAXALT, Nevada 

ALAN CRANSTON, California 
JOHN A. DURKIN, New Hampshire 

Larry Gage, Counsel 
Jay B. Cutler, Minority Counsel 

(II) 



k, 



FOREWORD 



The ongoing debate over marihuana has always been among the 
most schizophrenic of our national drug abuse policy issues. 

On the one hand, we are struggling toward an understanding of the 
complex dysfunctional effects of heroin on our society, and attempting 
vigorously to develop programs to reduce both the supply and demand 
of this, as well as other dangerous illicit drugs. 

In addition, we are taking a cold, hard look at many of our pre- 
scription and over-the-counter drugs, asking whether there needs to 
be further restrictions or more rigorous controls over man}' of them, 
due to the adverse health consequences they may well entail. 

We are looking with disfavor, for example, upon our increasing 
reliance on tranquilizers and other anti-depressant drugs. We are 
viewing with alarm the hawking of over-the-counter remedies during 
popular, child-oriented television programs, commercials which teach 
our children that one drug is better than another for a headache — 
but not (as psychiatrist Gerald Shulman pointed out in recent hear- 
ings) that a headache is a perfectly natural way for the human body 
to express its own momentary need for relaxation and quiet, and that 
dulling the pain could sometimes be the worst possible solution to that 
type of medical problem. 

We are worried, in short, about becoming a chemical culture, a na- 
tion of people whose solution to every little problem is a drink or a 
pill. 

Only with regard to marihuana, on the other hand, do ''liberal" 
minds appear to be moving in the opposite direction. 

Many States are considering the decriminalization of the possession 
of marihuana, and some have already enacted such laws. 

For the first time, national survey* data indicate that a majority of 
persons in the 18 to 25 age bracket have tried marihuana. Thus, even 
if the drug is to become completely legal, as is alcohol or tobacco, it 
would be even more important for us to understand as many of its 
potential health consequences as is possible. For it is important to 
bear in mind that, while heavy penalties for possession or use do not 
themselves create (or even necessarily reflect) sinister medical dangers 
from a substance, neither does legalization or decriminalization magi- 
cally remove any such dangers, if they actuallv exist. 

It is imperative, then, regardless of our opinion about decriminali- 
zation, that we continue our inquirv into the health consequences of 
marihuana use and abuse. This Fifth Annual Report makes many 
valuable contributions to that inquiry. 

Harrison A. Williams. Jr., 

Chairman, 
(in) 



Digitized by the Internet Archive 
in 2013 



http://archive.org/details/marihuanahunit 



LETTER OF TRANSMITTAL 



U.S. Senate, 
Committee on Labor and Public Welfare, 

Washington, B.C., July 21, 1976. 

Hon. Harrison A. Williams. Jr., 

Chairman, Committee on Labor and Public "Welfare, DirTcsen Senate 
Office Building, Washington, D.C. 
Dear Mr. Chairman : I am pleased to transmit to you the fifth an- 
nual report by the Secretary of Health, Education, and Welfare on 
Marihuana and Health. The annual publication of this report is re- 
quired by Title V of Public Law 91-296. It contains the latest scientific 
findings on the health consequences of marihuana use. This report has 
proven to be a valuable educational tool and policy guide to inform 
the public on the issues surrounding the effects of using (and abusing) 
marihuana. 

I am pleased, therefore, to transmit Marihuana and Health, Fifth 
Annual Report to the U.S. Congress from the Secretary of Health, 
Education, and Welfare to you and to recommend its distribution by 
the Committee. 
Sincerely, 

William D. Hathaway, 
Chairman, Subcommittee on 

Alcoholism & Narcotics. 

(V) 



ACKNOWLEDGMENTS 

As has been true in the past, preparation of the fifth annual Mari- 
huana and Health Report was made easier by the generous cooperation 
of the many members of the scientific community who supplied useful 
information on their current marihuana research. Their contribution 
is gratefully acknowledged. 

The technical chapters were written by knowledgeable members of 
the research community who generously gave of their time on short 
notice to maintain a tight production schedule. They are : 

Dr. Sidney Cohen, University of California at Los Angeles, Chap- 
ter 9, Therapeutic Aspects ; 

Dr. Douglas Ferraro, University of New Mexico, Albuquerque, 
Chapters 4, 5 and 6, dealing with preclinical unlearned and learned be- 
havior and with chronic effects on both ; 

Drs. Lissy Jarvik and Steven Matsuyama, University of Califor- 
nia at Los Angeles, Chapter 8, Effects on the Genetic and Immune 
Systems ; 

Dr. Reese Jones, Langley-Porter Neuropsychiatry Institute, San 
Francisco, Chapter 7, Human Effects ; 

Dr. Ralph Karler, University of Utah, Chapters 2 and 3, dealing 
with Chemistry and Metabolism and with Toxicological and Pharma- 
cological Effects ; and 

Dr. William McGlothlin, University of California at Los Angeles, 
Chapter 1, Epidemiology of Marihuana Use. 

Scientists on the staff of the National Institute on Drug Abuse who 
contributed to the report in a variety of ways include : Drs. Monique 
Braude, Norman Krasnegor, Daniel Lettieri, William Pollin, Joan 
Rittenhouse, Louise Richards, Stephen Szara, Robert Willette and 
Ms. Eleanor Carroll. 

Thanks are also due to Ms. Georgette Semick, Carol Tuckerman and 
Dr. Michael Rumsey for their editorial and production skills. 

Dr. Robert C. Petersen wrote the summary of the Report and as 
senior editor had primary responsibility for its overall preparation. 

(VI) 



CONTENTS 



Pago 

Foreword iii 

Letter of Transmittal v 

Acknowledgements vi 

Introduction 1 

Marihuana and health, 1975 : Summary and overview 3 

Technical chapters: 

1 . Epidemiology of marihuana use 17 

Present patterns and changes in use 17 

Social and psychological correlates 22 

References 25 

2. Chemistry and metabolism 27 

Drug sources 28 

Analytical techniques: Detection 28 

Metabolism 30 

References 32 

3. Toxicological and pharmacological effects 35 

Toxicological effects 36 

Pharmacological effects 39 

References 46 

4. Preclinical effects: Unlearned behavior 51 

Gross behavior 51 

Activity and exploration 52 

Consummatory behavior 53 

Aggressive behavior 54 

References 57 

5. Preclinical effects: Learned behavior 61 

Avoidance learning and aversive control 61 

Reinforcement schedules and maze learning 62 

Discrimination learning 64 

References 66 

6. Preclinical chronic effects: Unlearned and learned behavior 69 

References 72 

7. Human effects 75 

Acute effects 75 

Cannabis and psychopathology 84 

Chronic effects 88 

References 91 

8. Effects of marihuana on the genetic and immune systems 99 

Animal studies 99 

Human studies 100 

Summary and conclusion 104 

References 106 

9. Therapeutic aspects 109 

The Ancient Lore 110 

The Middle Period 111 

The Current Period 112 

Summary 119 

References 120 

Indexes : 

Author index 123 

Subject index 121 

(VH) 



INTRODUCTION 

Marihuana, an issue once marked by emotionalism, is increasingly 
being examined thoughtfully. Much has been learned about mari- 
huana use and its personal and social consequences. Yet, much remains 
to be understood. It is clear that marihuana is not a subject for sim- 
plistic analysis. 

This present edition of "Marihuana and Health" represents the fifth 
in a series of annual reports from the Secretary of Health, Education, 
and Welfare to the Congress as required by Title V of Public Law 
91-296. Last year, the fourth report in this series raised fundamental 
questions about the role of cannabis in altering the body's immune 
response, endocrine functioning and basic cell metabolism. Although 
more data are now available, the direct health implications of these 
earlier laboratory findings are still not certain. 

There is little question that marihuana intoxication, like alcohol 
intoxication, poses significant hazards. For example, psychomotor per- 
formance is impaired by cannabis intoxication. This can have dan- 
gerous consequences in such areas as traffic safety and industrial per- 
formance. Intellectual performance and in particular, immediate mem- 
ory, are also impaired while under the influence of the drug. Since 
marihuana is the third most widely used recreational drug — exceeded 
only by alcohol and tobacco — any adverse implications of its use are 
likely to be far-reaching. 

It has become increasingly clear that marihuana use is inextricably 
bound up with the use of many other drugs. Those who use other licit 
and illicit drugs are far more likely to use marihuana than those who 
do not. Conversely, heavy marihuana users are more likely than those 
who are not, to use other drugs as well. While it was once thought, for 
example, that marihuana users were less likely to use alcohol than non- 
users, it is now evident that they are, in fact, more likely to do so. 
Frequently the two drugs are used simultaneously — a combination that 
may be more hazardous than either used alone. 

The increasing availability of higher potency materials makes it 
more likely that adverse consequences will ensue if the use of these 
stronger cannabis preparations becomes widespread. 

This report does not give marihuana a "clean bill of health," as some 
would hope. Nor does it support the fear and irrationality that still 
characterize some of the public debate about marihuana. Instead, it is a 
progress report on our effort to understand a challenging health prob- 
lem with immense social, political, and economic implications. 

This year, in order to provide a somewhat broader perspective, the 
report is being issued as a general overview accompanied by a series of 
technical chapters which discuss the research findings in greater detail. 
In this manner we hope to better serve the needs of both the general 
reader and the research specialists. 

Robert L. DuPont, M.D., 
Director ', National Institute on Drug Abuse. 

(i) 



SUMMARY 

Marihuana and Health, 1975: Summary and Overview 
extent and nature of use 

Present evidence indicates that cannabis use has significantly in- 
creased among Americans during the last two years. 

Throughout most of its history American marihuana use has con- 
sistently involved a minority of any national age group ; however, the 
most recent national survey data indicate that in the 18-25 age group 
a majority (53%) have now tried the drug, up from 48% in 1972. 
Among those surveyed under 18, nearly one in four (23%) has ever 
tried marihuana — an increase from the one in seven (14%) who re- 
ported in the 1972 survey ever having done so. 

Current use — defined as use within the past month preceding the 
survey — has also significantly increased among those under 18. Seven 
percent reported such use in 1972, 12% did so in the most recent survey. 
There does not appear to have been a similar increase in such use 
among those over 18 — among whom current use has remained the same 
or has slightly diminished depending on age. since 1972. 

When questioned regarding their plans for future use, one third of 
those who have used marihuana indicate they definitely intend to do 
so again. Another third of this group indicate they might do so. 
Slightly smaller numbers of adults than of youths indicated their in- 
tention to continue use ( 1-1 ) . 

While there has been an increase in use by high school and junior 
high school age groups ( attested to by both local and national survey 
results), future trends of marihuana use in America continue to be 
uncertain. Despite the other increases noted, use among adults has not 
increased. In part, this may be explained by research reported in the 
fourth Marihuana and Health report : changes such as marriage, 
parenthood and the assumption of other adult roles are inimical to 
continued marihuana use. 

Support for the above interpretations is also found in data garnered 
from research conducted on a national sample of 20-30 year old men. 
This nationwide survey found that even within this restricted age 
group, larger proportions of the men in the younger subgroups used 
marihuana than did those who were older. Men pursuing more conven- 
tional life styles in that they were married and employed full time, 
were considerably less likely to be using marihuana than were either 
the unmarried or the unemployed (1-23) . 

Although there is good evidence of a continuing increase in mari- 
huana use among younger people, there is little indication that such 

Note. — Numbers In parentheses refer to the several technical chapters and their lists 
of references. Thus. 1-1 refers to reference one in Chapter 1. This is the specific study from 
which the data are abstracted. 

(3) 



use has come to involve a significant proportion of the older popula- 
tion. For example, if we examine the behavior of those ages 26-34, 
in contrast to the 18-25 age group less than one third (29%) have ever 
used marihuana compared to over half (53%) of the younger group. 
One in four of the 18-25 group had, in fact, used in the month pre- 
ceding the survey but less than one in twelve (8%) of those 26-34 had 
done so. In still older age groups use is even less common. Only 7% of 
those between 35^9 have ever used and only 2% of those over 50 have 
ever done so. Less than one in one hundred of the over 35 group had 
used during the month prior to the interview (1-1) . 

Despite the indications that marihuana has not become popular with 
older groups and the evidence that its use may be diminished as adult 
roles are adopted, any prediction regarding the future of cannabis in 
American society must be hedged with caution. A Gallup poll con- 
ducted in 1967 among college students indicated that only one in twenty 
had ever used the substance, but by 1974 over half (55%) reported use 
in the Gallup survey (1-9). In seven years, what was once clearly 
statistically deviant behavior has become the norm for this age group. 
While in previous years use was correlated with level of education, the 
percentage now reporting marihuana use is virtually identical for high 
school drop-outs, high school graduates and college graduates in simi- 
lar age ranges. 

National trends and use patterns mask distinctly different patterns 
in particular communities or geographical areas. In one Northern 
California county in which a survey of junior and senior high school 
students has been conducted each year since 1968, even the earliest 
findings indicated over one quarter of the ninth grade males (27%) 
had had some experience with marihuana during the previous year. 
Among male seniors nearly half (45%) reported use in the year pre- 
ceding. Current (1975) comparable figures are now 49% for ninth 
graders and 64% for senior boys. However, the percentage reporting 
use on 50 or more occasions in the previous year has not markedly in- 
creased for the past five consecutive years (1971-1975) (1-4). 

During the past five years since the first Marihuana and Health re- 
port, cannabis use in the United States has changed in character. Origi- 
nally marihuana's popularity was concentrated among young people 
associated with a "counter culture." It was regarded as symbolic of 
their opposition to traditional values and to the prevailing political 
climate (Cf. the first Report, 1971). 

As use has spread to involve larger numbers and to more conserva- 
tive segments — it has now been experienced by a majority in many 
groups — it has lost some of its nontraditional, antiestablishment sym- 
bolism. Early use often involved opposition to more traditional alcohol 
use. Xow those who use marihuana are also very likely to use alcohol — 
frequently simultaneously. Marihuana use seems unlikely to displace 
more traditional alcohol use even among the young. Continuing re- 
search on patterns of multiple drug use and drug using contingencies 
may better enable us to predict both individual and group drug use. 

Dee patterns in oilier countries, even those in which cannabis use 
has been endemic for many years, provide few clues to future use in 
the United States. In other countries use is typically class related with 
the lower classes, the traditional users. While in some of these conn- 



tries of traditional use tlrere are now middle or upper class users, such 
users seem to have adopted marihuana as part of an international 
youth culture rather than by diffusion from native users. Expectations 
with respect to drug effects also differ in that traditional users do 
not share the recreational orientation that characterizes American 
users. 

CHEMISTRY AND CHARACTERISTICS OF CANNABIS 

Although a detailed discussion of developments in cannabinoid 
chemistry is of primary interest to the specialist, there is a range of 
developments of more general interest. The plant, cannabis sativa, far 
from being a simple substance is, in fact, chemically quite complex. 
The last several years of research have resulted in an increasingly 
sophisticated knowledge about this complex substance. There is a grow- 
ing awareness of the need to much more adequately describe several 
major cannabis constituents if we are to adequately specify the nature 
of the material. The United Xations has now recommended that all 
research reports on cannabis describe not only the amount of delta-9- 
tet rahy drocannabinol (the major psychoactive ingredient) but that of 
cannabidiol and cannabinol as well. 

The ability to synthesize various chemical components of mari- 
huana as well as the drug's metabolites (i.e., compounds resulting from 
the biological transformation of the originally ingested material) is a 
significant advance. Availability of such pure substances provides re- 
searchers with necessary materials for careful study of the physio- 
logical role of marihuana's various components. 

While primary interest has tended to center on delta-9-THC because 
of its role as the principal psychoactive ingredient in cannabis, the 
part pla} T ed by several other ingredients may be important in produc- 
ing other cannabis effects. These other ingredients alone or in combina- 
tion, may account for possible adverse health consequences or con- 
tribute to the possible therapeutic usefulness of the, drug. 

The detection and analysis of marihuana in body contents such as 
blood, saliva, urine and breath is a problem important both to basic 
research and to forensic medical applications. For research, it is im- 
portant to deA'elop methods that accurately determine how much 
smoked or otherwise ingested marihuana actually becomes physio- 
logically available. These amounts ma}' be substantially different than 
the amount ingested because of losses that occur in consuming mari- 
huana, delayed bodily absorption, and individual differences in ability 
to metabolize the drug. 

In the clinical setting, appropriate treatment of the unconscious 
patient brought to the Emergency Boom following an accident may be 
dependent on knowing whether he or she is marihuana intoxicated. In 
other medical situations being able to determine with certainty the 
level or fact of being intoxicated may make the diagnosis of the 
patient much easier. 

The general increase in marihuana use has undoubtedly brought 
with it an increase in the numbers who drive while cannabis intoxi- 
cated. Recent evidence (Cf. Driving Effects) further confirms cannabis 
adverseh T affects driving. Thus, there is a real need for the develop- 
ment of one or more roadside methods that can be rapidly employed 
in much the same way as current tests for alcohol intoxication. 



6 

Although simple, rapid detection methods are badly needed, detect- 
ing marihuana use is inherently much more difficult than detecting 
alcohol use. The quantities of drug involved are much smaller and 
they are very rapidly transformed into metabolites which differ chemi- 
cally from the originally consumed material. As with alcohol, it is 
important to quantify the level of use for all of the purposes outlined. 
During the past year considerable progress has been made in improv- 
ing detection techniques. 

In addition to newer, thin laved chromatography and high pressure 
liquid chromatography methods, two other techniques have shown un- 
usual promise. Radioimmunoassay (RIA) is a technique in which an 
antibody specific to a drug or its metabolites is developed and then 
"tagged" by means of a radioactive molecule in its structure. When 
a solution of the tagged antibodies and of the body fluid in which the 
drug to be detected is made, the radioactive markers are displaced 
proportionately to the drug quantity present. The accuracy of RIA 
is now being compared with that of more cumbersome procedures. 

A second technique under development is called the enzyme multi- 
plied immunoassay test, or EMIT. The antibody reaction which is its 
basis is similar to that used in the radioimmunoassay technique. 
EMIT has the added advantages of involving less work, less sophisti- 
cated equipment and is more rapid thus making it more suitable for 
rapid screening. Field trials on EMIT are ongoing. 

A third method which also shows promise of shortly becoming 
available is likely to be most useful for traffic safety purposes. It 
utilizes breath samples in a manner roughly analogous to present road- 
side alcohol intoxication detection. 

As has been repeatedly emphasized, marihuana and hashish vary 
widely in THC content and thus in their ability to intoxicate. This 
variability results from differences in plant genetic origin, conditions 
of cultivation and preparation of the material including the degree 
of concentration of leaves and flowering tops. A relatively recent addi- 
tion to the illicit market is hashish oil, a substance having a THC con- 
centration of 40-50% as compared to the 1-2% THC content of most 
marihuana ordinarily available in the United States. Increasing avail- 
ability of such more potent cannabis preparations may have quite 
different implications from the more commonly used, weaker prepara- 
tions that have been available in the past. Use of stronger material, 
particularly by relatively naive users unaccustomed to its effects, is 
considerably more likely to result in acute panic and other adverse 
reactions. Stronger cannabis and cannabis derival ives used under con- 
ditions in which the dose is more difficult to control, may also result 
in marked impairment in driving or other complex psychomotor skills. 
Such unexpected effects could have serious implications. 

ANIMAL RESEARCH 

A wide range of research on the effects of marihuana has been con- 
ducted with animals because their genetic and learning histories, un- 
like those of humans, can be accurately specified. Animal models also 
permit the use of high doses and other procedures not possible in 
human research. Apart from studies of various physiological effects 



of the drug which have been discussed primarily in relation to human 
findings, there are some behavioral observations in animals that are 
of interest. 

Because there has been some question about the role of marihuana 
as a possible releaser of aggression, studies of animal aggression fol- 
lowing marihuana or THC administration have been done. Generally, 
these drugs have been consistently found to suppress aggression when 
the animals are not under stress. "When animals are stressed by a 
variety of means (e.g., food deprivation, sleep deprivation, morphine 
withdrawal, etc.) THC or marihuana tends to increase aggression. 

The results of behavioral studies in animals suggest that the effects 
of cannabis on aggression may be complexly related to the degree to 
which the animal is subject to stress and the length of time over which 
it has received the drug. The degree to which these observations are 
relevant to human behavior is unknown although they do provide a 
basis for devising related human studies. 

In an experiment which studied monkeys in three to six member 
social groups several changes of interest were found. Given oral doses 
equivalent to very heavy human cannabis use. the monkeys responded 
much like humans. They slept and rested more frequently ; active social 
interaction such as grooming of others was reduced. Over more ex- 
tended periods of administration, the monkeys gradually showed less 
and less of these effects. While aggression was initially reduced, after 
receiving THC for weeks or months during the year-long study the 
monkeys became irritable and aggressh^e (hitting, biting, chasing be- 
havior increased). There was no evidence of the reduction in testos- 
terone levels that has been reported in humans nor were menstrual 
cycles of females apparently disturbed (4—67). 

More detailed discussion of the extensive research that has been 
done with animals is to be found in the technical chapters of this report. 

HUMAN EFFECTS AXD HEALTH IMPLICATIONS 

Effects of marihuana can conveniently be divided into : (1) the acute 
effects of cannabis intoxication and (2) the longer range consequences 
of regular or chronic use. It is considerably easier to study acute effects 
and so after eight years of intensive investigations many, if not most, 
of these effects have been elucidated. 

Human acute physiological effects 

An increase in heart rate and a reddening of the eyes have been the 
most consistently reported physiological effects of marihuana. Heart 
rate increases are closely dose related. Early awareness of this mari- 
huana-induced tachycardia created concern over possible adverse car- 
diovascular effects of the drug especially in those with coronary disease. 
Several reports issued in the past year have confirmed a preliminary 
finding from last year. Marihuana use decreases exercise tolerance 
prior to the onset of chest pain (angina) in those with heart disease 
(7-137, 3, 4). Use of those with already existing cardiovascular defi- 
ciencies, therefore, appears to be unwise. The contrasting finding that 
marihuana produces minimal changes in heart function ( aside from a 
rate increase) in young, healthy men illustrates that the drug's effects 



may significantly differ in persons with pre-existing medical problems 
from those in normals. 

A number of reports have confirmed and extended initial evidence 
that smoked marihuana when acutely administered, results in improved 
pulmonary function as measured by bronchodilation (7-156, 157, 158). 
Optimism created by this finding has since been tempered by evidence 
that under conditions of more chronic use pulmonary function is im- 
paired, rather than enhanced (7-62) . 

Evidence that marihuana and especially its principal psychoactive 
ingredient, delta-9-THC, are effective in reducing intraocular pres- 
sure in both normals and in glaucoma patients has been further con- 
firmed. While some question exists whether this effect is due to a non- 
specific drug-induced relaxation shared with other sedative drugs or 
to a more specific marihuana reaction, more recent evidence suggests 
it is THC-specific (Cf . Therapeutic Aspects) . 

Understanding of the metabolism and the mechanisms of action re- 
sponsible for various marihuana effects has increased although many 
questions remain open. 

More sophisticated attempts to measure various aspects of psycho- 
logical and psychomotor performance have been generally consonant 
with subjective reports. Impaired memory, altered time sense and per- 
formance decrements on a variety of tasks have been experimentally 
confirmed. Generally, the more complex the task, the greater the de- 
gree of disruption produced by acute intoxication. Tasks which are 
relatively simple and with which the person is familiar are minimally 
affected. As the task becomes more demanding and novel and/or the 
dose of drug increases, performance decrements become larger. At 
lower doses, evidence confirms users' assertions that they are often 
able to "suppress the marihuana high" when the situations so demand. 

Although users have reported enhanced auditory, visual and tactual 
awareness and sensitivity, experimental research has not confirmed 
these reports. 

Driver performance and traffic safety 

Because of the prominent role the automobile plaj^s in our society, 
the possible implications of marihuana intoxication for traffic safety 
have been emphasized. Early reports were more optimistic about driver 
performance than recent evidence. Those consuming alcohol to the 
level of legal intoxication were originally found to make significantly 
more driving errors in a driving simulator situation than those who 
had consumed a "social dose" of marihuana. While the marihuana- 
intoxicated subjects indicated that their drivimr performance was af : 
fected, they felt they could compensate by driving more slowly and 
cautiously. 

Present evidence, whether derived from driver test course perform- 
ance, from actual traffic conditions or from the experimental study 
of components of the driving task, all indicate that driving under the 
influence of marihuana is hazardous (7-00). The increasing simultane- 
ous use of both alcohol and marihuana by drivers poses a threat that 
may well exceed that of either substance alone. While ihc parameters 
of risk connected with the use of marihuana alone or in combination 
with alcohol prior to driving are not yet known, discouragement of 



9 

such use appears justified. A more accurate determination of the ex- 
tent of risk involved in the various levels of intoxification would be 
desirable. Such studies are complicated by individual differences but 
are by no means impossible to execute. 

Although there has been little systematic study of the relationship 
of marihuana smoking to possible pilot error, evidence related to 
driving is at least partially germane. Such skills as detection of pe- 
ripheral stimuli and complex psychomotor coordination involved in 
driving are probably equally important in flying. In fact, the inher- 
ently greater complexity of flying suggests that performance is even 
more likely to be impaired under conditions of marihuana intoxica- 
tion than is driving. Only one preliminary report of pilot performance 
has appeared in the research literature. This report indicates that 
under flight simulator test conditions experienced pilots show marked 
deterioration in their performance while marihuana intoxicated 
(7-108). More detailed studies are planned to better understand the 
nature of the performance deficits produced and their duration. A 
danger common to both driving and flying is that some perceptual 
or other deficits may persist for some time beyond the period of sub- 
jective intoxication. Under such circumstances an individual may 
attempt to fly or drive without realizing that his functioning is still 
impaired although he no longer feels "high." 

Chronic use — special froolem areas 

Last year's report singled out several special problem areas involv- 
ing potentially serious adverse consequences of chronic cannabis use. 
Subsequent research has not definitively resolved the questions raised 
but has expanded our knowledge base. 

Some apparent inconsistencies in research findings regarding re- 
duced plasma levels of the male hormone, testosterone, may be ex- 
plained by the differing length of time users had been smoking before 
such levels were assessed. For example, the findings of one study that 
did not show a decrease during a several week period were matched 
by those in another study in which there were early negative findings. 
However, after four weeks elapsed a definite drop occurred (7-100). 
The decreases that have been found have still been within what are 
generally conceded to be normal limits. Their biological significance 
remains in considerable doubt. A preliminary finding that a marked 
reduction of sperm count (58%) occurred in five cannabis smokers fol- 
lowing controlled conditions of smoking has been reported (7-171). 
While this poses the possibility of diminished fertility in chronic 
users, the small size of the sample and the study's preliminary nature 
make the work inconclusive. 

With regard to hormonal aspects, two other adverse effects remain 
possibilities : (1) Interference with normal growth and sexual develop- 
ment of adolescent heavy users and, (2) Abnormal sexual differentia- 
tion of the male fetus developing in a mother who heavily uses mari- 
huana during early pregnancy. Xo actual evidence for either of these 
speculative possibilities has yet appeared in the scientific literature. 

The question of a cannabis induced impairment of the body's im- 
mune response remains important because of its potentially far reach- 



7-061 



10 

ing clinical implications. While a number of investigators have 
published findings that suggest that marihuana may interfere with 
cell-mediated immunity* other investigators have not found such 
evidence. Some of these differences may reflect procedural variations; 
nevertheless, the clinical significance of the positive findings remains 
in considerable doubt. At least one study of experienced marihuana 
smokers under well-controlled, closed experimental ward conditions 
found initial evidence of impaired immunity upon their admission to 
the study. However, by the G3rd day of controlled cannabis adminis- 
tration, their immune response had apparently returned to normal 
(8-39). This finding suggests that the impairment of immunity ini- 
tially detected in these and other marihuana smokers may be related 
to factors other than marihuana use. 

The implications of laboratory findings of inhibition of DNA, RXA 
and protein synthesis, all basically related to cellular reproduction am! 
metabolism, are at present unknown. These findings based on in vitro 
(outside the body) study of animal and human tissue cultures are also 
being followed up and extended. 

Similarly, no conclusion evidence exists regarding damage to human 
genetic functioning (i.e., chromosomal damage produced by mari- 
huana). While the most carefully controlled studies have failed to 
demonstrate such damage, the research to date must be regarded as 
insufficient to permit definitive conclusions. 

Presently, preliminary evidence of a range of potentially serious 
consequences of marihuana use exists. As indicated, these include: 
Disruption of basic cell metabolism through interference with DNA 
and 1\XA synthesis, possible interference with pituitary function, in 
turn, affecting testosterone production and possibly having other en- 
docrine effects and interference with the body's disease defenses by 
effecting the immune response. Despite this laboratory evidence, the 
clinical implications remain in doubt. While no evidence has appeared 
indicating that marihuana users here or abroad suffer from unusually 
high rates of infectious disease or cancer which might result from 
defects in the immune response, carefully controlled large scale clini- 
cal studies have not yet been conducted. Similarly, there is no evi- 
dence — but neither have there been adequate systematic studies — to 
establish whether users have significantly lower fertility rates or more 
serious problems with impotence than non-users. 

The failure to detect gross clinical findings that might be expect ed 
does not. of course, mean that these issues have been resolved. To date 
systematic studies of matched samples have been modest in size. Detec- 
tion of rarer consequences of use is less likely in studies of limited 
size and extent. As the number of chronically using Americans in- 
creases, larger scale epidemiological studies are becoming feasible. 
Plans for such studies are underway. 

OTHER CHRONIC HUMAN EFFECTS 

Tolerance cmd dependence 

Tolerance to cannabis — diminished response to a given repeated 
drug dose— luis been substantiated by research evidence. Development 

of tolerance to marihuana's effects was originally suspected because 



11 

of the obvious ability of cannabis users overseas to ingest larger quan- 
tities of the drug without disruptive effects than was possible for less 
experienced American users. Systematic, controlled studies in which 
known doses of marihuana or THC were administered over extended 
periods have now confirmed this (8-53, 80, 109. Ill) . 

The meaning of cannabis dependence is often somewhat vague. If 
Ave define it as a physical dependency manifested by physical symptoms 
following drug withdrawal, there is now evidence that it can occur. 
The symptoms that have been reported following discontinuance of 
high dose chronic administration of delta-9-THC include: Irritability, 
restlessness, decreased appetite, sleep disturbance, sweating, tremor, 
nausea, vomiting and diarrhea (8-80). It should be noted, however, 
that the after effects reported followed unusually high doses of orally 
administered THC under research ward conditions. Such changes have 
not commonly been observed in other studies nor has a ''withdrawal 
syndrome" typically been found among users here or abroad. 

Psycho pathological and neurological aspects 

The question of possible prolonged behavioral effects of chronic 
cannabis usage has been an area of fundamental concern throughout 
the American cannabis research program. As indicated in earlier re- 
ports, foreign observers have argued that a range of such effects occurs, 
including a specific cannabis psychosis, diminished intellectual per- 
formance and an "amotivational syndrome" (characterized by a loss of 
interest in work and other conventional activity). Interpretation of 
such reports has unfortunately been complicated by the lack of ade- 
quate control groups, poor research design, use of opium and other 
drugs, poor diagnostic criteria, nutritional deficiencies and other differ- 
ing factors of life style. 

Even when a particular consequence is correlated with marihuana 
use. it is often erroneously attributed to the drug use. A recent study 
of 38 first admissions to a psychiatric hospital illustrates the problem 
of interpretation involved : While there was a correlation between 
marihuana and subsequent psychiatric illness, it was less than with 
such causally unrelated variables as having danced and having drunk 
beer (7-2). 

The acute panic anxiety reaction, previously mentioned in the dis- 
cussion of acute effects, is probably the most common adverse reaction. 
However, a more prolonged cannabis psychosis has been reported in 
Eastern literature. It appears to occur under conditions of unusually 
heavy use or as a result of ingesting a larger amount than usual. De- 
scriptions do not always distinguish between an acute brain syndrome 
or toxic delirium marked by clouded mental processes, disorientation, 
confusion and marked memory impairment and a more prolonged 
psychotic reaction precipitated by cannabis use. Often it is difficult to 
isolate the causative role of marihuana from that of pre-existing ps} T - 
chopathology or other drug use (7-64, 112) . 

Three XIDA-supported research studies of heavy chronic users 
conducted in Jamaica. Greece and Costa Rica have 'failed to detect 
evidence for a cannabis psychosis. However, given the comparative 
rarity of this syndrome and the small sample sizes used, it is possible 
that such a consequence was missed. 



12 

Studies of college student performance have generally failed to 
prove evidence of impaired intellectual performance related to mari- 
huana use. 

While there was no evidence of differences in grade point average 
or in educational achievement, marihuana users in one major study 
had greater difficulties than non-users in deciding career goals and 
were more likely to have dropped out of college to reassess their goals 
(7-11). Some of these studies suffer from several shortcomings, how- 
ever; the samples studied may not have adequately emphasized college 
drop-outs thus excluding the very group that might have been most 
adversely affected by heavy use. A second consideration is that students 
typically have higher levels of ability than the general population. 
Particularly in more competitive academic environment, they may 
have above average motivation allowing them to better compensate 
for cannabis effects. Finally, even moderately heavy American student 
users use the drug less frequently, in less potent forms and in lesser 
quantity than more heavily using overseas populations. 

Assessing the psychosocial effects of marihuana use in chronically 
using populations can be complicated. Changes in values and behavior 
attributed to marihuana use may, in fact, have preceded use rather 
than the use affecting the change in values. Especialty in earlier years, 
users were much more likely to hold counterculture, antiestablishment 
views. For these users marihuana had symbolic value as a means of 
indicating their disdain for the prevailing value system. This disdain 
was frequently accompanied by a rejection of the traditional work 
ethic with its emphasis on competitive achievement. The group dy- 
namics of marihuana use may, however, reinforce these counterculture 
views of more conventional motivation rather than result from any 
pharmacological action of the drug itself. 

Similarly, attempts to create experimental models for testing the 
existence of such an "amotivational syndrome" have had serious limi- 
tations. Tasks chosen as tests may significantly depait from more real- 
istic work tasks; the artificial environment if the research setting 
may not provide more typical motivational conditions. Two studies 
involving marihuana administration coupled with monetary reward 
for work performance did find a decline in productivity with heavier 
marihuana consumption. In one the task was simple and relatively 
undemanding, involving repetitive button pushing that could be car- 
ried on simultaneously with other activity (7-111). In the other, a 
more typical work task — the making of wooden stools — was carried 
on (7-13). The distinction between a direct effect on performance as 
;i result of marihuana and on performance as a result of a decline in 
motivation is not easily made, however. In a third, quite limited 
study of agricultural performance undertaken in connection with the 
Jamaican study of chronic users, researchers found some decline in 
work performance although the decline was not dramatic (7-141). 

When one turns to the neurological evidence there is little question 
that there are acute effects of marihuana intoxication although these 
are not easily distinguished from those of other psychoactive drugs as 
measured by conventional elect roencephalograms. The EEG changes 
resulting from electrodes implanted deeply m the brain are dissimilar 
to other psychoactive drugs (7-67).. The behavioral significance of the 



13 

EEG changes that have been found in chronically using monkeys and 
in very limited human studies is not presently known. 

Work in Greece has not supported previously cited evidence sug- 
gesting that brain damage marked by enlarged ventricles may result 
from marihuana use. The Grecian study, using noninvasive echo- 
encephalographic techniques for measurement of ventricle enlarge- 
ment, found no evidence of such brain damage in heavily hashish 
using men matched with non-using controls (7^9) . 

Field studies of chronic users 

Although other portions of this and previous reports touch on one 
or another of the three Federally sponsored studies of chronic mari- 
huana use in Jamaica, Greece and Costa Rica, it may be useful to 
summarize their findings, strengths and weaknesses here. The Ja- 
maican study has been extensively reported in previous Marihuana 
and Health reports, a recently published book and in the research 
literature (7-141). A report on the Greek study was delayed in order 
to make the data base as complete as possible. The third study in Costa 
Rica was just completed: its detailed findings will be released by 
Spring, 1976. In each of these research efforts, an attempt was made 
to match drug-using subjects with appropriate nonusing counterparts. 
In the Jamaican and Costa Rican projects rather careful matching 
was done; in the Greek study such matching was less possible. All sub- 
jects were males because male use predominates in the cultures studied. 
Numbers of subjects were necessarily limited by the detailed pro- 
cedures followed (Jamaica: 30 experimental, 30 control; Greece: 47 
experimental, 40 control; Costa Rica: 40 experimental, 40 control, 
although 80 and 140 users and non-users respectively were actually 
examined). 

The Jamaican study found few physiological or psychological differ- 
ences between the matched smoker nonsmoker populations. A rather 
extensive battery of tests of physical and psychological functioning 
found no differences that could be directly attributed to marihuana 
use as such. "While an attempt was also made to assess chromosomal 
abnormalities, that portion of the study must be regarded as incon- 
clusive because of technical deficiencies in the methodology for that 
phase of the project. 

The Greek study arose from a clinical impression by Greek observers 
that Greek hashish users, because of their heavy use patterns and 
already established researcher-subject rapport, would make a good 
study population for examining the effects of unusually heavy cannabis 
use. 

A variety of neurological, psychological and physical measures 
found few changes attributable to cannabis use. Heavy emphasis was 
placed on possible brain damage as measured by electroencephalo- 
graphic, echo-encephalographic (Cf. preceding section) and psycho- 
logical test procedures. Xone of these measures showed evidence of 
brain damage (7-49). 

The most recent Costa Rican study also examined matched samples 
of users and non-users especially carefully matched on such variables 
as age, marital status, education, tabocca smoking and alcohol use. 
Emphasis was placed on extensive medical examinations with special 
attention to pulmonary and neuropsychological functioning. Although 



14 

detailed results have not yet been published, no evidence for a greater 
incidence of disease or of psychological deterioration has been found 
in the cannabis-using group (7-23) . 

Xonc of the three studies found evidence of increased psychopathol- 
ogy or of an amotivational syndrome stemming from the use of 
cannabis. 

While results of these studies must be regarded as somewhat reas- 
suring of the lack of grossly adverse consequences of marihuana use, 
they can not, of course, be regarded as conclusive for several reasons. 
All three studies involve relatively small numbers of subjects. Equally 
limited studies of cigarette smoking, for example, which is known to 
have serious adverse health consequences, would not have been likely 
to detect those consequences. Psychological testing techniques are less 
apt to be satisfactory when used with subjects markedly different from 
the original standardization samples. To the extent that they are not 
culture free, performance for both experimental and control groups in 
cultures unlike those on which they were standardized may both show 
a culturally derived deficit. This deficit may mask a drug-related defi- 
cit in performance. Thus, the tests used may not be sufficiently sensitive 
to detect a difference that may in fact exist. Finally, it may be argued 
that the demands of a less technologically oriented society are less com- 
plex than those of the industrialized United States. Thus, the failure 
to find a drug-related decrement in social or work performance may 
reflect an unimpaired ability to meet the demands of a simpler situa- 
tion that would not be true under more demanding circumstances. 

THERAPEUTIC ASPECTS 

Although cannabis has been used for over 3,000 years as a medicinal 
herb in native and scientific medicine, its use in Western medicine 
sharply declined in modern times. By the 1930s, American medicine 
had largely supplanted cannabis with more convenient and more stable 
pharmaceutical preparations. Our relatively recent concern with mari- 
huana as a drug of abuse has led to scientific investigation into its 
properties by means of modern pharmacological techniques. Synthe- 
sized constituents of the natural material have been produced enabling 
researchers to study the properties and effects of each of the compo- 
nents of this complex material. This recent study has reawakened scien- 
tific interest in possible therapeutic uses for the natural material or its 
synthesized ingredients. 

Although some of marihuana's properties — notably its psychoactiv- 
ity and its tendency to accelerate heart rate — are undesirable for most 
medicinal purposes, cannabis has one highly desirable property. Com- 
pared to most pharmaceuticals it is very low in biological toxicity. In- 
deed, it is questionable whether any deaths can be directly attributed 
to an overdose of marihuana or hashish. 

Whether or not cannabis or perhaps some modified constituent again 
becomes useful in medical practice will depend on whether some of 
the drug's promising therapeutic properties prove to be sufficiently 
persistent and its side effects controllable. Marihuana's usefulness as a 
medication for chronic disorders may also prove to be limited by the 
development of tolerance to its therapeutic effects. 



15 

The most promising therapeutic applications of the drug are in the 
treatment of glaucoma, as an anti-emetic for cancer patients receiving 
chemotherapy and possibly in the treatment of asthmatics. Other ap- 
plications as a sedative-hypnotic, an anticonvulsant, an antidepressant, 
an analgesic and in connection with the treatment of alcoholics have 
been attempted, but the results have either been inconsistent or highly 
preliminary. 

The use of cannabis and THC in treating the elevated intraocular 
pressures in glaucoma patients arose from the observation in normals 
that internal eye pressures were reduced by the drug. Subsequent re- 
search with patients has confirmed that the effect is also produced 
in the diseased eye and is as great as that produced b} 7 more traditional 
medications. Topical preparations applied to the eyes of rabbits have 
successfully reduced pressure raising the possibility of using such a 
preparation with humans. Human experimentation is not, however, 
expected in the immediate future because of the formidable problems 
in making certain that such a preparation is safe and can meet regula- 
tory requirements (9-12, 25, 26). 

The use of THC as an anti-emetic witli cancer patients receiving 
chemotherapy shows unusual promise. One of the undesirable side 
effects of chemotherapeutic agents administered to cancer patients is 
that they produce marked nausea and vomiting. This side effect is very 
difficult for patients to tolerate and is also debilitating. Standard anti- 
emetic drugs have not. unfortunately, been notably successful in re- 
ducing this side effect. THC, by contrast, was found in a recent double- 
blind study (neither patient nor physican knew whether the drug 
received was active or inert) to be effective in virtually all of the 
patients receiving it. While 13 of the 16 patients receiving the drug 
became "high'' and one third developed drowsiness, these effects were 
viewed as minor compared to the therapeutic benefit achieved (9-58). 

Use of THC in the treatment of asthmatics is predicated on the 
observation that it dilates pulmonary air passages and decreases air- 
way resistance (9-64). Based on observations in normal research with 
asthmatics has demonstrated that marihuana relieves bronchospasm 
and has a more persistent action than traditional medication (9-65). 
Since smoked marihuana has obvious lung irritant properties, more 
recent research has emploved aerosolized THC, also with promising 
results (9-46). 

There has been a growing awareness that constituents other than 
delta-9-THC may have valuable therapeutic properties if freed of some 
of the undesirable side effects noted with THC. It is also possible for 
the organic chemist to produce a very wide range of chemical com- 
pounds which are broadly based on the chemical structure of the 
cannabinoids, but with changes in that structure which can markedly 
alter their action. Such chemically more remote compounds may ulti- 
mately prove more useful therapeutically than either the natural mate- 
rial itself or its synthesized ingredients. Because they are not the 
parent compounds they must, of course, be carefully tested for toxicity 
and therapeutic properties like any other new compound. 



CHAPTER 1 

Epidemiology of Marihuana Use 

presext patterns and changes in use 

National household surveys {adult) 

The National Commission on Marihuana and Drug Abuse sponsored 
national household surveys of marihuana and other drug use in 1971 
and 1972 (2, 3). A third national survey conducted in late 1974 — early 
1975 provides a comparison with the earlier periods (1). (See Table 

Another national survey conducted for the Drug Abuse Council in 
1974 found very similar results. The percentages of adults (18 and 
over) reporting ever having used and currently using were 18 and 
8% respectively (24). As can be seen in Table A-l, the number of 
adults currently using marihuana has not changed appreciably in the 
past two years. Usage continues to be concentrated in the 18-25 age 
bracket and is about twice as frequent for males as females. 

Current usage is about equal for white and non-white groups. It is 
positively associated with education, and is highest for those now in 
college (33%). Current usage continues to be highest in the TTest 
(11%) and lowest in the South (4%), and higher in large metro- 
politan areas (9%) than in non-metropolitan regions (3%). However, 
all of these differences have become less pronounced in the past three 
years. 

Because of the relatively small numbers involved, national general 
population surveys do not provide very accurate estimates of changes 
in heavy marihuana use; nevertheless, some information is available. 
The 1971 Marihuana Commission survey reported daily or more fre- 
quent use among adults at 0.5%, while the comparable value for 1972 
was 1.4%. The follow-on survey in 1974 did not report the rate of daily 
use, but noted that adult usage of nine or more days in the past month 
was 2.7%. The 1974 Drug Abuse Council national survey reported 
1.5% of the adult sample used marihuana daily or more frequently. 
These limited data do not appear to indicate a change in adult daily 
usage in the past two years. 

National household surveys (youth) 

The results of the Marihuana Commission surveys of youth ages 
12-17 and the results of the 1974 follow-on studv are found in Table 
A-2. 

(17) 



18 



TABLE A-l— MARIHUANA USE AMONG ADULTS, 1971-74 (1, 2, 3) 



Percent ever used 



Percent current use ■ 



1971 


1972 


1974 


1971 


1972 


1974 


15 


16 


19 


5 


8 


7 


39 


48 


53 


17 


28 


25 


19 


20 


29 


5 ... 






9 


6 


7 


1 


1 


1 


6 


2 


2 ... 








21 


22 


24 


7 


11 


9 


10 


10 


14 


3 


5 


5 



All adults... 

Age: 

18 to 25 
26 to 30 
35 to 49 
50 plus. 

Sex: 

Male... 
Female. 



i Used during last month. 

TABLE A-2.-MARIHUANA USE AMONG YOUTH, 1971-74 (1, 2, 3) 



All youth.... 

Age: 

12 to 13 
14 to 15 
16 to 17 

Sex: 

Male... 
Female. 



Percent 


ever used 




Percent current use » 




1971 


1972 


1974 


1971 


1972 


1974 


14 


14 


23 


6 


7 


12 


6 


4 


6 


2 


1 


2 


10 


10 


22 


7 


6 


12 


27 


29 


39 


10 


16 


20 


14 


15 


24 


7 


9 


12 


14 


13 


21 


5 


6 


11 



i Used during last month. 

Another set of national household data collected in a Columbia 
University study reported quite similar results (8, 16) : 

Percent 
Age 12 to 17: ever used 

1971 15 

1972 15 

1973 17 

1974 to 1975 22 

Age 16 to 17: 

1971 28 

1972 31 

1973 32 

1974 to 1975 40 

However, the 1974 national survey conducted for the Drug Abuse 
Council reported considerably lower marihuana usage for 12-17 age 
group. 14% in the "ever used" category and 5% as "currently using" 
(24). This discrepancy may have been related to the relatively small 
sample size of 505. This survey also utilized "rider questions" attached 
to a larger unrelated survey. 

The Marihuana Commission surveys in 1971 and 1972 reported daily 
marihuana usage for the 12-17 age group at 0.6% and 1.3% respec- 
tively. The follow-on 1974 survey found 4.4% indicated usage of nine 
or more times in the past month. The 1974-75 national survey for the 
Columbia University study found 2% of youth ages 12-17 and 4% 
of those either 16 or 17 years of age reported using marihuana 60 or 
more times within the two-month period. While the percentage of 
daily use was not reported for the earlier years, the 1974 Drug Abuse 
Council survey reported daily or more frequent usage by 1% of 12-17 
age group and 3% of those 16^-17. 



19 

Student surveys 

A longitudinal study of high school males followed from their senior 
year to five years after graduation provides an indication of changes 
in marihuana usage over time in the same group (14, 15). The sample 
of over 2,000 was selected from 87 public high schools so as to be 
representative of American males entering high school in 1966. (Data 
arrayed in Table A-3.) 

Another study surveyed drug usage in 22 selected high schools 
throughout the United States in 1971 and 1973 (16). These data are 
not necessarily representative of the student population, but do pro- 
vide an indication of changes in marihuana use over the two-year pe- 
riod. (Table A-4) 

A survey of 16,000 male and female high school seniors in 130 
schools, selected to be representative of public and private high schools 
throughout the country, was conducted in 1975 (15) and is to be re- 
peated on an annual basis. The percentage of high school seniors re- 
porting marihuana usage in the 1975 survey were: 



TABLE A-3.— PERCENTAGE OF MARIHUANA USE AMONG A NATIONAL SAMPLE OF HIGH SCHOOL MALES (14, 15) 



Senior year, 
1969 


1 year after 

graduation, 

1970 


5 years after 

graduation, 

1974 


Ever used... .... .. 20 


35 

33 

9 

2 




fi? 


Any use in prior year 20 


5? 


Daily or weekly sometime in prior year... 6 


21 


Daily use sometime in prior year 1 


9 


TABLE A-4.— PERCENTAGE OF MARIHUANA USE REPORTED IN 22 HIGH SCHOOLS (16) 


Junior high school 


Senior high school 




1971 1973 


1971 




1973 



Everused... 15 19 38 48 

Ever used 60 or more times 2 4 11 17 

Used in past 2 months 11 13 27 36 

Used 60 or more times in past 2 months 112 4 

Percent 
Ever used 47 

Used in last 12 months 41 

Used in last month 29 

Used 20 or more times in last month 6 

The only regularly conducted national survey of marihuana use 
among college students is that prepared by Gallup (9). The percent- 
ages reporting having ever used this substance in surveys conducted 
between 1967 and 1974 were : 

Percent 

1967 5 

1969 22 

1970 42 

1971 51 

1974 55 

One other national student survey conducted in 1974-75 for Drug 
Abuse Council found 48% of high school and 64% of college students 



20 

reported having used marihuana (33, 34). The corresponding percent- 
ages for daily use were 6% and 8%. 

One local survey of particular interest is that annually conducted 
among high school students in San Mateo County, California since 
1968 (4). Table A-5 shows the percentage of ninth and twelfth grade 
male students reporting one or more, ten or more, and 50 or more 
uses of marihuana during the preceding year. 

San Mateo County is adjacent to San Francisco, and thus had an 
earlier and more pronounced exposure to the counterculture movement 
and associated drug use than did most other areas. This is particularly 
evident in the figures for the late 1960's. For instance, one year after 
Gallup found only 5% of nationwide college students had used mari- 
huana (1967), the comparable percentage for senior males in San 
Mateo county high schools was 45%. The percentage of San Mateo 
students using marihuana in 1975 is still substantially above the na- 
tional level ; however, the difference is not nearly so large. It is interest- 
ing to speculate on the meaning of this narowing gap. One possibility 
is that the apparent plateau may be a ceiling and that the growth of 
marihuana use in San Mateo may have reached its limit. It may also 
be that other drugs (viz cocaine) , not of great interest when the study 
began in 1967, are now luring users away from marihuana. Many alter- 
native explanations for the San Mateo phenomenon are possible; 
whether the phenomenon or its alternate interpretations have any 
meaning for the national level is unknown. 

In summary, at the national level marihuana use appears to have 
significantly increased among youth during the past two years. This 
is indicated by the trend in national household surveys as well as 
surveys of various high school student populations. This conclusion 
is contrary to that suggested in the 1974 Marihuana and Health report, 
when data available at that time seemed to indicate a plateau had been 
reached (20). It also appears that daily marihuana use has increased 
among youth, although the available data on changes in daily use are 
fairly limited. 

TABLE A-5.-PERCENTAGE OF MARIHUANA USE AMONG MALE SAN MATEO 
COUNTY HIGH SCHOOL STUDENTS (4) 





1 or more uses 


in past year 


10 or more uses 


in past year 


50 or more uses 


in past year 




9th grade 


12th grade 


9th grade 


12th grade 


9th grade 


12th grade 


1968 


27 


45 
50 


14 
20 


26 
34 


NA 
NA 


NA 


1969. 


35 


NA 


1970 


34 


51 


20 


34 


11 


22 


1971 


44 


59 


26 


43 


17 


32 


1972 


44 


61 


27 


45 


16 


32 


1973 


51 


61 


32 


45 


20 


32 


1974 


49 


62 


30 


47 


20 


34 


1975 


49 


64 


30 


45 


20 


31 



THarihuand use among males, age 20 to 30 

One of the most significant recent studies involved the interviewing 
of ^.500 selected to be representative of the 19,000,000 U.S. males in the 
20-.°>0 age group (2D) . This group evidences the highest rate of drug 
use, ami the in-depth interviewing of a relatively large representative 



21 

sample provided more reliable information on marihuana and other 
drtrg-usrftg behavior than had previously been available. 

The data were collected from October, 1974 to May, 1975 and showed 
that 55% of those interviewed had at some time used marihuana. De- 
fining as current use any use in the year 1974—1975, the study reported 
§8% current users. Fifteen percent reported having used marihuana 
daily or almost daily at some time. Eleven percent reported using 
marihuana 1,000 or more times, and 11% also reported use within 24 
hours of the interview. Hashish use at some time was reported by 29%, 
and the use of hashish oil by 11%. Surprisingly, 11% of the total 
sample and 41% of those described as heavy users reported growing 
marihuana for their own use. 

When particular age categories within this group are examined, the 
data show that 37% of the men who were 29-30 at the time of the 
interview had used marihuana in comparison to 63% of the 20-24 age 
group. When those described as light or experimental marihuana users 
are excluded, the differences are even more striking; 12% of those 29- 
30 reported use in comparison to 37% of those 20-24. These results 
indicate that males now in their late twenties are less likely to have 
tried marihuana than men five to ten years younger, and are con- 
siderably less likely to adopt marihuana use as a frequent behavior. 
Similar or more pronounced differences probably exist for those over 
30. For instance, the 1974 follow-on to the Marihuana Commission 
Survey found 7% of males and females aged 34-49 reported having 
used marihuana, but only 1% had done so within the past month. 

The peak year of first marihuana use for the sample of males be- 
tween 20 and 30 was 1969 ; however, the peak year for any use during 
the calendar year was 1974 when the rate for this group reached 37 %. 
The authors concluded that the data were clearly consistent with an 
upward trend in marihuana use. 

This study also revealed that the differences in marihuana use as a 
function of various demographic characteristics were not as pro- 
nounced in the group sampled as those reported in the general popula- 
tion. In the male 20-30 age group, 70% of those living in cities of over 
1.000,000 population had used marihuana in comparison to 43% of 
tho>e in communities of less than 2,500. In terms of education, the 
percentage reporting some use of marihuana was almost identical for 
those with less than high school education, high school graduates and 
college graduates. Those who had attended college without graduating 
showed a higher rate. For those aged 20-23 at the time of the inter- 
view, the percent having used marihuana was virtually the same for 
those still in school and those not. A higher percentage of blacks (65%) 
than whites (54%) reported some use, but the inverse relation of mari- 
huana use to age was not as apparent in the black group. Blacks and 
other ethnic minorities showed a higher prevalence of marihuana use 
prior to the late 1960s, but minority youth were less influenced by the 
recent epidemic (5). 

A synthesis 

The overall survey results indicate that marihuana use has not sig- 
nificantly penetrated the portion of the adult population over 30 years 
of age. Where use has occurred in this group, the frequency has been 



22 

mostly of an experimental nature. However, the plateau in current 
marihuana use among adults found in national survey results may be 
deceptive in predicting future usage. As the more frequently using 
younger groups enter the adult age range, the overall rates are likely 
to increase. 

Results from both household surveys and student studies indicate 
that marihuana use is still increasing among youth at the national 
level, although usage appears to have stabilized in certain areas which 
reached a relatively high level in the early 1970's. Most of the data on 
youth also indicate that daily or near-daily usage has increased in the 
past two to four years. 

If recent marihuana usage in the United States is compared with 
that prior to the epidemic which began in the late 1960's or especially 
with patterns of use in countries where cannabis use has been indige- 
nous for many years, some useful perspectives emerge. It is clear that 
much of the recent American usage is quite minimal, both in terms of 
frequency of use and amount consumed (21, 27). The patterns of use 
often seem to be based more on the adoption of a fad or style than an 
attraction to the pharmacological properties of the drug. This is not 
to say that, once it is introduced as a fad, marihuana use will not be 
sustained because of its pharmacological effects. 

Based on currently available survey data, it appears that around 
2% of youth, aged 12-17 or about 8% of those who have tried it, are 
currently using marihuana daily. For those 17 years-of-age, around 
4 or 5% are probably daily users and for 17-year-old males the per- 
centage is of the order of 6 or 7%, or about 13% of those having 
tried it. 

For adults, the overall daily use is probably only 1 or 2%, but a 
more meaningful percentage is that for the age groups primarily in- 
volved. As described earlier, the percentage of daily use among males 
20-30 years of age is around 8 or 9% or 15% of those who have tried 
marihuana. For males 20-24 years of age, current daily use is around 
10 or 11%, or about 17% of those having ever used the drug. 

SOCIAL AND PSYCHOLOGICAL CORRELATES 

Research on the social and psychological correlates of marihuana 
use may be organized under three headings: 1) pre-use characteristics; 
2) factors influencing transition from non-use to use, including the 
temporal order of drug-using behavior; and 3) correlates of mari- 
huana use following its adoption. In most instances only statistical 
associations, as opposed to casual relationships, can be established. 

Pre-nse ch aracterist/cH 

This aspect has been thoroughly covered in earlier research and 
recent work lias largely served to confirm prior findings. Aside from 
the associaf ion of marihuana with rout ine demographic variables such 
as those mentioned in the previous section, the majority of variables 
which predict marihuana use, ranging from a break with traditional 
values (7. 10, 19) to more severe behavioral and adjustment problems 
(11) are related to lack of conformity. Smith has found self and peer 



23 

ratings of rebelliousness to be among the best predictors of high school 
students who subsequently become marihuana users (29). 

Factors influencing transition from non-use to use 

In a longitudinal study of high school students, Jessor has shown 
that those individuals who will initiate marihuana use can be identified 
with considerable accuracy from various personality, belief and atti- 
tude measures (13). Furthermore, these measures, such as attitude 
toward deviance, value of achievement and friends' approval of drug 
use, show significant changes in the direction of the user group during 
the period of marihuana initiation. Jessor has found similar results 
with regard to the initiation of alcohol drinking and sexual behavior. 

Several studies have investigated the role of child-rearing practices 
and parents' drug-using behavior in the initiation of adolescent drug 
use. One recent study found that perceived laissez-faire parent-child 
relationships led to high marihuana usage among the offspring; an 
autocratic relationship led to medium usage : and quasi-democratic or 
democratic relationship led to low usage (12). Another study found 
higher rates of marihuana use when the parents showed less dis- 
approval of use. and also when the father used prescription drugs (25) . 
Kandel also found a positive relationship between parents' drug-using 
behavior and the child's marihuana use, although her work demon- 
strated rather conclusively that this effect was minor in comparison to 
peer group influence (17). This emphasis on peer influence is in ac- 
cord with the thesis of Suchman and others that student marihuana 
and other drug use is largely determined by the integration into a 
social subculture in which drug use is a part (31, 32) . 

One social environment, the military, has apparently proved to have 
less influence on marihuana and other drug use than was initially be- 
lieved. O'Donnell, et al., in their study of 20-30 year old males found 
that neither domestic nor overseas service had any effect on marihuana 
use (23). Robins has also found that Vietnam veterans' marihuana use 
after return was not significantly increased over that for a comparison 
group who did not enter the military (26) . 

Since marihuana use is known to generally precede other illict drug 
usage, the question is often raised as to the role of marihuana in facili- 
tating the transition or progression to more dangerous drugs. While 
not specifically answering this question, Kandel and associates have 
determined that the temporal sequence along the legal-illegal drug con- 
tinuum is consistent (18, 28). By conducting longitudinal studies of 
two large samples of high school students, they were able to determine 
the order in which the various drugs were used. Only 1% of the sample 
began using illicit drugs without first using a legal drug. Beer and 
wine collectively constituted by far the most common "entry drug" 
(28%) with cigarettes accounting for 6% and hard liquor 3%. In 
addition to the fact that legal drug use virtually always preceded illicit 
use, heavy use of both liquor (weekly) and cigarettes (over a pack a 
day) resulted in a high percentage (40%) moving from non-use to use 
of illicit drugs in a five month period. Only 2 to 3% of adolescent legal 
drug users progressed to other illicit drugs without first trying mari- 
huana. If the individual progressed beyond marihuana, the next step 



24 

was generally pills. Subsequent steps were psychedelics, cocaine and 
heroin, in that order ; but, of course, only a small percentage progressed 
to the higher levels in the sequence. Heavy use of marihuana or other 
drugs along the sequence was more often followed by progression to 
the next step, and also by a higher probability of moving two or more 
steps during a single time period. 

Correlates of marihuana use 

Although marihuana use has become increasingly common over the 
past several years, it is not surprising that those who are less conven- 
tional in other respects are more likely to use the drug than are the 
more traditionally oriented. In their national study of males, ages 20- 
30, O'Donnell et al., found that those men living in consensual unions 
(i.e., with a woman to whom they are not married) were more likely 
to be using marihuana than those living independently, or living in 
their parental home. Those who were married and living with their 
wives were least likely to be using the drug (the percentages of current 
use in ascending order were : married, 25% ; living with parents, 38% ; 
living independently, 56%; consensual union, 68%). A similar trend 
was found in the use of other drugs including alcohol and tobacco (i.e., 
current drug use of all types was greater by males in consensual unions 
than among those who were married). Those unemployed at the time 
of interview were more likely to have used marihuana in some time in 
their lives than those who were employed (72% of the unemployed had 
ever used compared to 52% of the employed) (23) . 

In this same stud}' both self-reported criminal acts and contacts 
witli the criminal justice system (some drug use related) were sub- 
stantially higher for marihuana users than for the non-users. The 
authors caution, however, that "the fact that drug use sometimes 
occurs first and at other times criminal behavior precedes use indi- 
cated that if there is a causal connection between drug use and crimi- 
nal behavior, it is not a simple one"' (23). Similar results have been 
reported in terms of arrests by Brill and Christie (1% for non-users 
compared to 10% for regular marihuana users) (6). 

An Air Force study of some 4500 men reporting marihuana use 
indicated somewhat poorer performance when compared with a control 
group of non-users (22). Finally, a longitudinal study of college 
freshmen found a strong relationship between marihuana and other 
drug use and the choice of unconventional careers (30). There was also 
a disproportionate tendency for marihuana users to change in the 
direction of unconventional careers during the two-and-one-half year 
follow-up period and the authors concluded, after multivariate analy- 
sis, that the results suggest a causal relationship. However, it should 
l>e stressed that, in general, studies relating marihuana use to other 
variables have not established more than a statistical association. It is 
cleat- that marihuana usage is frequently part of a larger pattern of 
nonconformity, but the existence of causal relationships between mari- 
huana use mikI other behavior have generally not been determined. 



References. — Epidemiology of Marihuana Use 

1. Abelson, H. and Atkinson, R. B. "Public Experience with Psychoactive 
Substances." Princeton, New Jersey : Response Analysis Corporation, August, 
1975. 

2. Abelson, H., Cohen, R. and Schrayer, D. A nationwide study of beliefs, in- 
formation and experience. "Marihuana : A Signal of Misunderstanding." Na- 
tional Commission on Marihuana and Drug Abuse; Appendix Volume II. Wash- 
ington, D.C. : Government Printing Office, 1972. 

3. Abelson, H., Cohen, R., Schrayer, D. and Rappeport, M. Drug experience, 
attitudes and related behavior among adolescents and adults. "Drug Use in 
America : Problem in Perspective." National Commission on Marihuana and Drug 
Abuse ; Appendix Volume I. Washington D.C. : Government Printing Office, 1973. 

4. Blackford, L. "Student Drug Use Surveys — San Mateo County, California 
1968-1975." San Mateo, California : Department of Public Health and Welfare, 
1975. 

5. Bloom, R., Hays, J. R. and Winburn, M. G. Marihuana use in urban secondary 
schools : A three year comparison. "The International Journal of the Addictions," 
9:329-335 (1974). 

6. Brill, N. Q. and Christie, R. L. Marihuana use and psychosocial adaptation. 
Follow-up study of a collegiate population. "Archives of General Psychiatry," 
31:713-719 (1974). 

7. Cunningham, W. H., Cunningham, I. C. M. and English, W. D. Sociopsycho- 
logical characteristics of undergraduate marijuana users. "The Journal of Ge- 
netic Psychology," 125 :3-12 (1974) . 

8. Elinson, J. "A Study of Teenage Drug Behavior." NIDA Grant DA 00043. 
Columbia University School of Public Health, New York, N.Y., October, 1975. 
Personal communication. 

9. "Gallup Opinion Index." Volume 109 (Part 4). Princeton, New Jersey: 
American Institute of Public Opinion, 1974. 

10. Grossman, J. C, Goldstein. R. and Eisenman, R. Undergraduate marijuana 
and drug use as related to openness to experience. "Psychiatric Quarterly," 48 
(1) :86-92 (1974). 

11. Halikas, J. A. and Rimmer, J. D. Predictors of multiple drug abuse. "Archives 
of General Psychiatry." 31 :414-418 (1974). 

12. Hunt, D. G. Parental permissiveness as perceived by the offspring and the 
degree of marijuana usage among offspring. "Human Relations," 27(3) :267-285 
(1974). 

13. Jessor, R. Predicting time of onset of marijuana use : A development study 
of high school youth. "Journal of Consulting and Clinical Psychology," in press. 

14. Johnston, L. D. Drug use during and after high school : Results of a national 
longitudinal study. "American Journal of Public Health" (Supplement), 64:29- 
37 (1974). 

15. Johnston, L. D. "Monitoring the Future: Continuing Study of Life Styles 
and Values of Youth." University of Michigan, Ann Arbor, October, 1975. Per- 
sonal communication. 

16. Josephson, E. Trends in adolescent marijuana use. "Drug Use : Epidemio- 
logical and Sociological Approaches." Edited by Josephson, E. and Carroll, E. 
Washington, D.C. : Hemisphere Publishing Corporation, 1974. 

17. Kandel, D. Inter- and intragenerational influences on adolescent marijuana 
use. "Journal of Social Issues," 30(2) : 107-135 (1974). 

18. Kandel, D. and Faust, R. Sequence and stages in patterns of adolescent drug 
use. "Archives of General Psychiatry," 32 :923-932 (1975) . 

19. Krug. S. E. and Henry, T. J. Personality, motivation, and adolescent drug 
use patterns. "Journal of Counseling Psychology," 21(5) : 440-445 (1974). 

20. "Marihuana and Health." Fourth Annual Report to Congress from the 
Secretary of Health, Education, and Welfare. Washington, D.C. : Government 
Printing Office, 1974. 

(25) 

67-062—76 3 



26 

21. McGlothlin, W. H. Drug use and abuse. "Annual Review of Psychology," 
26:45-64 (1975). 

22. Mullins, C. J., Vitola, B. M. and Michelson, A. E. Variables related to 
cannabis use. "The International Journal of the Addictions." 10(3) : 581-502 
(1975) 

23. O'Donnell, J. A., Voss, H. L., Clayton, R. R., Slatin, G. T. and Room, 
R. G. W. "Non-Medical Drug Use Among Young Men in the United States : A 
Nationwide Survey." Special Action Office for Drug Abuse Prevention Grant DA 
3AC678 and NIDA Grant DA 01121, 1975. 

24. Opinion Research Corporation, "Use of Marijuana and Views on Related 
Penalties Among Teens and the General Public." Commissioned by the Drug 
Abuse Council, Washington, D.C., October, 1974. 

25. Prendergast, T. J. Family characteristics associated with marijuana use 
among adolescents. "The International Journal of the Addictions," 9(6) : 827- 
839 (1974). 

26. Robins, L. N. "Veterans Drug Use Three Years After Vietnam." Special 
Action Office for Drug Abuse Prevention Grant DA 3AC680, NIDA Grant DA 
01120, and NIMH Grant MH 36,598, 1975. 

27. Rubin, V. and Comitas, L. "Oanja in Jamaica : Medical Anthropological 
Study of Chronic Marihuana Use." The Hague : Mouton, 1975. 

28. Single, E., Kandel, D. and Faust, R. Patterns of multiple drug use in high 
school. "Journal of Health and Social Behavior." 15(4) : 344-357 (1974). 

29. Smith, G. E. Early Precursors of Teenage Drug Use. Paper presented at the 
36th Annual Scientific Meeting, Committee on Problems of Drug Dependence, 
Mexico City, 1974. 

30. Somers, R. H., Mellinger, G. D. and Manheimer, D. I. "Drug Use and Career 
Choice Among University Men." XIDA Grant DA 00137, "Institute for Research 
in Social Behavior." 16(1) : 63-72 (1975). 

31. Suchman, E. The hang-loose ethic and the spirit of drug use. "Journal of 
Health and Social Behavior," 9 :146-155 (1968). 

32. Thomas, C. W., Petersen, D. M. and Zinggraff, M. T. Student drug use : A 
re-examination of the "hang-loose ethic" hypothesis. "Journal of Health and 
Social Behavior," 16(1) : 63-73 (1975). 

33. Yankelovich, D. Drug users vs. drug abusers — how students control their 
drug crises. "Psychology Today," 9(5) : 39-42 (1975). 

34. Yankelovich, D. Yankelovich, Skelly, and White, Inc., New York, N.Y., 
October, 1975. Personal communication. 



CHAPTER 2 

Chemistry axd Metabolism 

Because the drug abuse problem involves marihuana, the study of 
the pharmacological and toxicological properties of the drug must be 
pursued ; cannabis, however, is a complex mixture of variable amounts 
of numerous, potentially active substances. The chemistry of mari- 
huana is. therefore, of paramount importance to the investigator, and 
the recently reported development of relatively simple analytical pro- 
cedures for the separation and quantitation of the major cannabinoids 
in marihuana is a significant advance. The effects of marihuana can 
now begin to be more meaningfully compared in different laboratories, 
and many of the past problems of conflicting data will be avoided 
simply by knowing the chemical composition of the sample at hand. 
Indeed, the United Nations has recommended that all research reports 
on the properties of marihuana include a quantitative account of the 
major cannabinoid content of the preparation involved. 

Another notable contribution in the field of cannabinoid chemistry 
was the introduction of a refinement in the synthesis of delta-9-THC, 
the major psvchoactive drug in cannabis. In recent years, the synthesis 
of delta-9-THC, as well as of other cannabinoids, has been subjected 
to extensive investigation, which has resulted in a continuous simplifi- 
cation of the synthetic procedures. Such developments have reduced 
the cost of synthesis and thereby increased the availability of these 
important drugs for scientific investigation. The long-term significance 
of the recent refinement must be viewed in the perspective of a long 
list of many contributions to our understanding of the chemistry of 
cannabis and its constituents. In the past few years the chemical study 
of cannabis has resulted in the isolation, characterization and synthesis 
of numerous constituents of marihuana, thus providing biologists with 
the opportunity to study the pure drugs. In a classical sense, the chemi- 
cal advances represent the basis for the rational investigation of the 
pharmacology and toxicology of marihuana. 

Xew reports of the isolation and identification of some of the metabo- 
lites of marihuana continue to represent the most important aspect of 
research in the area of metabolism. In the human, for example, can- 
nabinol has now been reported as a metabolite, and several new ones 
have been isolated from urine. It is essential to pursue the identifica- 
tion of marihuana metabolites because the question of what accounts 
for the pharmacological and toxicological activity of marihuana can 
only be answered by a study of the constituents of cannabis and their 
respective metabolites. The importance of metabolism was first demon- 
strated a few years ago when ll-hydroxy-delta-9-THC, a major 
metabolite of delta-9-THC, was found to be as active as, or more 

(27) 



28 

active than, the parent compound. In the current Marihuana and 
Health report, the study of the anticonvulsant activity of the can- 
nabinoids has revealed that another metabolite, 8-alpha, 11-dihydroxy- 
delta-9-THC, is also a very active substance. It is not unreasonable to 
assume that still other marihuana metabolites will be found to produce 
significant pharmacological and toxicological effects. 

DRUG SOURCES 

The detailed chemical analysis of cannabis has been extended to 
yield more components (4, 43, 44), and investigators have recently 
identified a new spermidine alkaloid called cannabisativine in an alco- 
holic extract of the root of Cannabis saliva L. (24). 

The importance of the influence of smoking marihuana on the nature 
of its chemical constituents continues to be recognized (14, 18, 19, 20, 
37). A detailed analysis of the pyrolytic products of cannabidiol 
(CBD) has demonstrated that one of the principal volatile products 
formed is olivetol, a pharmacologically active chemical precursor of 
the cannabinoids (19). 

The camiabinoids are potentially unstable compounds and their 
stability in chloroform, a commonly used solvent for extraction and 
storage of camiabinoids, has been re-examined (51) : The results of a 
three-month storage study support a previous assessment that either 
synthetic or naturally occurring cannabinoid mixtures are reasonably 
stable. Other investigators have determined the influence of pH on 
stability by describing the kinetics of the degradation of delta-9- and 
delta-8-tetrahydrocannabinol (delta-9-THC, delta-8-THC) at differ- 
ent pH values (12) . 

More new cannabinoids have been synthesized and examined for 
pharmacological activity (8, 22, 52) , and the synthesis of delta-9-THC 
has continued to be refined with the introduction of a one-step reaction 
using either chrysanthenol (35) or p-mentha-2,8-dien-l-ol and olivetol 
(34). 

ANALYTICAL TECHNIQUES: DETECTION 

At the present time four principal methods are used for the analysis 
of cannabinoids: gas-liquid chromatography (GLC), thin-layer chro- 
matography (TLC), mass spectroscopy (MS) and radioimmunoassay 
(RIA). The chromatographic procedures remain the most useful be- 
cause they offer either simplicity, as in the case of TLC, or the best 
con ib ination of sensitivity and selectivity, as in the case of GLC. The 
GLC methods have been especially useful in the separation and quanti- 
tat ion of cannabis constituents (31). One of these methods, which in- 
volves the formation of silyl derivatives of 2% OV-17 chromatog- 
raphy columns (49) , has been extremely valuable for the elucidation of 
the major components of cannabis. This method, referred to in the 1974 
Marihuana and Health report (25), demonstrated that previous GLC 
analyses of cannabis failed to separate CBD from cannabichromene 
(CBC) : hence, some CBD samples used in pharmacological studies 
were probably significantly contaminated with CBC. The recognition 
01 the prevalence of CBC in some cannabis samples should prompt a 
re-evaluation of the pharmacological effects of pure CBD and an evalu- 



29 

ation of the pharmacological properties of CBC, alone and in combina- 
tion with CBD. 

The variability in cannabis composition has led the United Xations 
to recommend that all scholarly reports on the effects of cannabis in- 
clude a quantitative analysis for CBD, cannabinol (CBX), and delta- 
9-THC content : the GLC method described above was recommended 
for this purpose. Subsequently, the same research group published 
another GLC method which does not require derivatization, but still 
provides satisfactory separation of CBD and CBC (50). The relative 
simplicity of this procedure suggests that it is the current method of 
choice for the analysis of cannabis for its principal cannabinoid 
constituents. 

Xew TLC methods for the cannabinoids continue to be developed (9, 
16, 17, 29, 48). A two-dimensional TLC system has been described as 
capable of separating 27 constituents of hashish resin, including CBD, 
CBX, delta-9-THC and CBC (29). This technique uses silica-gel 
plates and the solvents n-pentane-diethyl ether-ethyl acetate (90 : 8 : 2) 
and n-pentane-aceton (90 : 10). In another report a new procedure for 
extracting urine enables the cannabinoid metabolites to be separated 
into neutral, weak and strong acid fractions, which can be easily frac- 
tionated further by TLC (17). In addition, the use of methanol to 
extract della-9-THC and its metabolites from tissues was found to 
yield higher recoveries than other common extraction methods (38). 
Finally, the factors that influence the stability and color intensity of 
the chromogcn-cannabinoid products have been identified as chromo- 
gen basicity, residual solvent and chromogen dyestuff (9). 

High pressure liquid chromatography (HPLC) represents a new 
and potentially useful technique for cannabinoid analyses. The great 
separatory capability inherent in HPLC should lend itself well to the 
general problem of resolving complex cannabinoid mixtures. A recent 
report has described the use of dansyl derivatives for the fluorometric 
detection of cannabinoids separated by HPLC (1). The results ob- 
tained from the analysis of cannabinoid standards illustrate that the 
combination of dansyl derivatives and HPLC provides a method with 
the sensitivity and selectivity of GLC and mass fragmentography. 
This method has recently been used effectively in an examination of 
cannabinoid metabolites in dog feces (23). Furthermore, it is interest- 
ing to note that HPLC has been used to separate quantitatively delta- 
9-THC from other plasma heptane extractable substances (e.g., lipids) 
that can interfere with the GLC analysis of such extracts (11). 

Since the pioneer mass spectroscopy work with cannabinoids by 
Agurell, et al. (56). which was summarized in the fourth Marihuana 
and Health report (25). the technique has played an important role 
in the identification of individual cannabinoids. The inherent sensi- 
tivity of the technique lends itself well to the potential measurement 
of cannabinoids in biological samples; and workers at the Research 
Triangle Institute have developed a method for the quantitative anal- 
ysis of human plasma for concentrations of delta-9-THC as low as 0.5 
ng/ml (58). Mass fragmentographic methods have also been used in 
a number of other studies (16, 23, 29, 43, 44, 57) . 

Several reports have also appeared describing the use of RIA for the 
detection af cannabinoids, particularly in body fluids (13, 26, 46, 47). 



30 

In addition, two new immunoassay techniques are under consideration : 
homogeneous enzyme immunoassay (36) and free radical immunoassay 
(6). The most appealing feature of immunoassay is its great sensi- 
tivity, but limited selectivity continues to restrict its applicability. 

METABOLISM 

The continuing study of the biological disposition of the cannabi- 
noids has yielded a greater understanding of factors affecting their 
metabolism, the nature of their metabolites, their distribution in the 
body and, finally, the routes of their excretion. Research into hepatic 
microsomal metabolism was designed to define the optimal in vitro 
conditions for the metabolism of delta-9-THC (40). The influence of 
several cannabinoid vehicles on delta-9-THC metabolism was evalu- 
ated, and apparent Km and Vmax values were determined. The pat- 
tern of metabolite production was followed as a function of duration 
of incubation. 

Twenty-four hours after oral administration, crude cannabis resin 
was found to increase both pulmonary and hepatic aryl hydrocarbon 
hydroxylase activity in male rats (42). The stimulus for this effect 
may have been the trace quantities of benzo- (alpha) -pyrene found in 
cannabis resin. In another experiment, the rate of delta-9-THC metabo- 
lism both in vivo and in vitro was increased by the daily pretreatment 
of rats with phenobarbital (39). Despite an increased rate of metabo- 
lism, neither the apparent Km nor Vmax was altered. The pheno- 
barbital effect was compared with the response in tolerant animals: 
In vitro, the rate and pattern of metabolism was unchanged, and, in 
vivo, the amounts of cannabinoid in tissue and its disappearance from 
blood was also unaffected. The data suggest a functional, rather than 
a dispositional, basis for tolerance. 

Various drugs have been examined in terms of their effects on the 
in vitro and in vivo metabolism of delta-9-THC (41) : Pentobarbital, 
phenobarbital, SKF 525-A, amphetamine and meprobamate all in- 
hibited delta-9-THC metabolism in vitro; under similar conditions 
morphine and mescaline had no effect. In contrast to these general 
findings, only SKF 525-A affected delta-9-THC metabolism in vivo. 
It appears, therefore, that the in vivo interactions between delta-9-THC 
and other centrally acting drugs cannot be explained by an alteration 
in delta-9-THC metbolism. 

Recent examinations of the dolta-9-THC biotransformation prod- 
ucts of rabbit and dog liver microsomes have revealed the presence of 
1,2-epoxyhexahydrocannabinod (3, 55) ; and a comparison of metabo- 
lites from the perfused dog lung and from dog hepatic microsomes 
has led to the discovery of side-chain hydroxylated derivatives (55). 
Moreover, there is now evidence that CBN and its oxidized derivatives 
are normal metabolites of delta-9-THC. CBN" lias been identified in 
human plasma following marihuana smoking (27), in rat bile (54) 
and in rat blood (28) after intravenous injection of delta-9-THC. 
Oxidized metabolites of CBN have also been identified (2, 5) ; and a 
new metabolite containing two carbdxy] groups has been isolated from 
rabbit urine (30). Both rat and rabbit liver microsomes were found 
to convert CBN into a number of side-chain hydroxylated compounds 



31 

(53). In addition, marihuana metabolites in human urine have been 
extracted by a new method which separates them into neutral, weak 
and strong acid fractions (17). 

Various aspects of the distribution of the cannabinoids in the body 
have been investigated : Thus, one research group has found that the 
properties of delta-9-THC in plasma are a function of the method of 
administering the drug (10). In this study, delta-9-THC was admin- 
istered either intravenously in polyethylene glycol or in rat serum, 
or in the form of cannabis smoke. Plasma disappearance curves varied, 
depending upon the method of administration, and, compared with the 
other two means of administration, injection in serum resulted in a 
slower elimination from plasma, a lower proportion of metabolites rela- 
tive to delta-9-THC and a different distribution of binding to plasma 
proteins. 

Other investigators found that the plasma-protein distribution of 
delta-9-THC after intravenous administration differs in female and 
male rats (7) : and at all doses tested, the response in females was more 
pronounced. The latter finding correlated with that of higher tissue 
concentrations of delta-9-THC and its metabolites in the female; 
therefore, the enhanced activity of delta-9-THC in the female rat may 
be due to the higher tissue cannabinoid concentrations in the brain. 

The relationship between tissue-drug concentration and pharma- 
cological activity was extended in a comparative study of the effects 
of delta-9-THC and dimethvlheptopvran (DMHP) on mouse im- 
mobility (21). Like delta-9-THC, the brain concentrations of DMHP 
and its hydroxylated metabolite correlated with the behavioral effect 
(21). Despite DMHP's greater potency, the fraction of the dose in 
the brain was smaller than that of delta-9-THC ; thus, the potency dif- 
ference between delta-9-THC and DMHP appears to be a consequence 
of the latters greater activity at the site of action. 

Plasma concentrations of delta-9-THC, ll-hydroxy-delta-9-THC, 
CBN and CBD were measured by radiommunoassay as a function of 
time after their intravenous administration in the rabbit (45). Delta- 
9-THC was unlike the other drugs, because plasma values for reacting 
substances rose for several minutes after injection, presumably due to 
the rapid formation and re-entry of the 11 -hydroxy metabolite into the 
plasma. In humans, this metabolite leaves the plasma more rapidly than 
does delta-9-THC (33) ; an observation that has been confirmed in mice 
(32). m 

In a study of lactating ewes, both delta-9-THC and its metabolites 
were recovered from the milk for as long as 96 hours after administra- 
tion of a single, intravenous low dose (15). Other investigations have 
shown that biliarv excretion in rats accounts for the elimination of 
60% of an intravenous dose of delta-9-THC (3mg/kg) (40), that 
biliary excretion remains unchanged when tolerance to THC develops 
(39), and, finally, that most of the metabolites in the bile are highly 
polar substances. 



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(32) 



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20. Kuppers, F. J. E. M., Berciit, C. A. L., Salemink, C. A., Lousberg, R. J. J. 
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cannabinol in mice. "Biochemical Pharmacology," 23: 3017-3027 (1974). 

22. Loev, B., Dienel, B., Goodman, M. M. and Van Hoeven, H. Synthesis of a 
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24. Lotter, H. L., Abraham, D. J., Turner, C. E., Knapp, J. E., Schiff, P. L., Jr. 
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Printing Office, 1974. 

26. Marks, V., Teale, D. and Fry, D. Detection of cannabis products in urine 
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27. McCallum, X. K. The determination of cannabinol levels in the blood and 
interpretation of their significance. "Pharmacology," 11 : 3337 (1974). 

28. McCallum, X. K., Yagen, B., Levy, S. and Mechoulam, R. Cannabinol : A 
rapidly formed metabolite of delta-1- and delta-6-tetrahydrocannabinol- "Experi- 
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29. Mobarak, Z., Zaki, X. and Bieniek, D. Some chromatographic aspects of 
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30. Xordqvist. M.. Agurell, S., Binder. M. and Xilsson, I. M. Structure of an 
acidic metabolite of delta-1-tetrahydrocannabinol isolated from rabbit urine, 
"Journal of Pharmacy and Pharmacology," 26:471-473 (1974). 

31. Parker. J. M. and Stembal, B. L. Review of gas-liquid chromatography of 
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32. Perez-Reyes, M., Simmons, J., Brine, D., Kimmel, G. L., Davis, K. H. and 
Wall, M. E. The rate of penetration of delta-9-tetrahydrocannabinol and 11-OH- 
delta-9-tetrahydrocannabinol to the brain of mice. Paper presented at the Sixth 
International Congress of Pharmacology, Helsinki, Finland, 1975. 

33. Perez-Reyes. M.. Timmons, M. C, Lipton. M. A.. Christensen, H. D., Davis, 
K. H. and Wall, M. E. A comparison of the pharmacological activity of delta- 
9-tetrahydroeannabinol and its monohydroxylated metabolites in man. "Experi- 
entia," 29:1009-1010 (1973). 

34. Razdan, R. K., Dalzell, H. C. and Handrick, G. R. Hashish. A simple one- 
step synthesis of <-)-delta-l-tetrahydrocannabinol (THC) from p-mentha-2, 
8-dien-l-ol and olivetol. "Journal of the American Chemical Society," 96 :586G- 
5865 (1974). 

35. Razdan, R. K., Handrick, G. R. and Dalzell. H. C. A one-step synthesis of 
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36. Rubenstein, K. "Homogeneous Enzyme Immunoassay for Cannabinoids," 
Contract Report ADM-45-74-166, June, 1975. 

37. Salemink. C. A. Pyrolysis of cannabinoids. Paper presented at the Sixth 
International Congress of Pharmacology, Helsinki, Finland, 1975. 

38. Schoolar, J. C, Ho, B. T. and Estevez, V. S. Comparison of various solvent 
extractions for the chromatographic analysis of delta-9-THC and metabolites. 
Paper presented at the Sixth International Congress of Pharmacology, Helsinki, 
Finland, July, 1975. 

39. Siemens, A. J. and Kalant, H. Metabolism of delta-1-tetrahydrocannabinol 
by rats tolerant to cannabis. "Canadian Journal of Phvsiologv and Pharma- 
cology." 52:1154-1160 (1974). 

40. Siemens, A. J. and Kalant. H. Metabolism of delta-1-tetrahydrocannabinol 
by the rat in vivo and in vitro. "Biochemical Pharmacology," 24:755-761 (1975). 

41. Siemens, A. J., deXie, L. C, Kalant, H. and Khanna, J. M. Effects of 
various psychoactive drugs on the metabolism of delta-1-tetrahydrocannabinol 
by rats in vitro and in vivo. "European Journal of Pharmacology," 31 : 136-147 
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34 

42. Skelton, F. S. and Witschi, H. P. Aryl hydrocarbon hydroxylase activity 
induced by cannabis resin : Analysis for polycyclic hydrocarbons. "Toxicology 
and Applied Pharmacology," 27:551-557 (1974). 

43. Stromberg, L. Minor components of cannabis resin IV. Mass spectrophoto- 
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with retention times shorter than that of cannabidiol. "Journal of Chroma- 
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44. Stromberg, L. Minor components of cannabis resin V. Mass spectrophoto- 
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with retention times shorter than that of cannabidiol. "Journal of Chromatog- 
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45. Teale, J. D., Clough, J. M., Piall, E. M., King, L. J. and Marks, V. Plasma 
cannabinoids measured by radioimmunoassay in rabbits after intravenous injec- 
tion of tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, cannabinol and 
cannibidiol. "Research Communications in Chemical Pathology and Pharma- 
cology," 11:339-342 (1975). 

46. Teale, J. D., Forman, E. J., King, L. J. and Marks, V. Radioimmunoassay 
of cannabinoids in blood and urine. "Lancet," 2 : 553-555 (1974) . 

47. Teale, J. D., Forman, E. J., King, L. J., Piall, E. M. and Marks, V. The 
development of radioimmunoassay for cannabinoids in blood and urine. "Journal 
of Pharmacy and Pharmacology," 27:465-472 (1975). 

48. Tewari, S. X., Harpalani, S. P. and Sharma, S. C. Separation and identi- 
fication of the constituents of hashish (cannabis indica linn.) by thin-layer 
chromatography and its application in forensic analysis. "Mikrochimica Acta," 
Part 6:991-995 (1974). 

49. Turner, C. E., Hadley, K. W., Henry, J. and Mole, M. L. Constituents of 
Cannabis sativa L. VII : Use of silyl derivatives in routine analysis. "Journal of 
Pharmaceutical Sciences," 63:1872-1876 (1974). 

50. Turner, C. E., Hadley, K. W., Ilolley. J. H., Billets, S. and Mole, M. L. 
Constituents of Cannabis sativa L. VIII: Possible biological application of a 
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51. Turner, C. E. and Henry, J. T. Constituents of Cannabis sativa L. IX: 
Stability of synthetic and naturally occurring cannabinoids in chloroform. 
"Journal of Pharmaceutical Sciences," 64:357-358 (1975). 

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epoxide cleavage by phenolate anion. Synthesis of novel and biologically active 
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Svensk Farmaceutisk Tidskrift, Scientific Edition," in press. 

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Biliary excretion of delta-1-tetrahydrocannabinol and its metabolites in the rat. 
"Biochemical Pharmacology," 23:1163-1172 (1974). 

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media by mass spectroscopy. NIDA contract ADM-45-74-109 (1974). 



CHAPTER 3 

TOXICOLOGICAL AND PHARMACOLOGICAL EFFECTS 

The toxicological research reviewed in the present Marihuana and 
Health report is the result of the continuing need to identify and 
evaluate the toxicological properties of marihuana. To fill this need, 
a series of inhalation toxicity studies have made two major contribu- 
tions. First, in the absence of detailed pathological studies in humans, 
marihuana has been administered to numerous species in a wide ranger 
of dosages by a variety of routes — including inhalation. The report 
that chronic administration of low doses by smoke inhalation results 
in a toxicity comparable to that elicited by other routes of administra- 
tion serves to validate the conventional animal toxicity studies which 
are based on either the oral or parenteral route. Accordingly, the mass 
of animal data collected in the past few years leads to the conclusion 
that, to date, regardless of the route of administration, the observed 
toxicity of marihuana is not associated with any serious pathological 
changes. 

Secondly, until the inhalation studies, most cannabinoid toxicity 
research was restricted to the principal psychoactive constituent of 
cannabis, delta-9-THC : now. however, cannabidiol and cannabi- 
chromene — both formerly considered pharmacologically inactive — are 
known to contribute significantly to the toxicity and lethality of 
marihuana. Clearly, future toxicological evaluations of cannabis con- 
stituents must be extended to all the major, naturally occurring canna- 
binoids. both alone and in various combinations. 

Another important aspect of toxicological research arises from the 
reported effects of marihuana on such cellular components and prod- 
ucts as lipids, proteins, nucleic acids, hormones and neurochemical 
transmitters. Am association between some of these effects and animal 
behavior has now been made: most, but not all, of the changes appear 
to be readily reversible. These cellular effects and their implications 
are not easily understood, but they may reflect subtle alterations in 
function independent of any gross pathological changes. With chronic 
drug exposure, however, these subtle changes may evolve into signifi- 
cant toxicological factors. 

The study of the pharmacological properties of marihuana is impor- 
tant for at least three reasons: (1) to define its effects, particularly 
its possible toxic effects: (2) to determine the potential interaction 
of its effects with various pathological states (e.g., coronary artery 
disease, liver disease, epilepsy) ; and (3) to evaluate the potential 
therapeutic uses of the cannabinoids. During the past year there have 
boen significant contributions to the attainment of all these objectives. 
Several studies have recognized the ability of the cannabinoids to 
interact, not only with one another, but more importantly, with other 

(35) 



36 

drugs ; the interaction in some instances results in the enhancement of 
a drug effect, in others in an antagonism. Such a complex set of effects 
has been described in the case of the barbiturates, the amphetamines 
and alcohol. The signficance of this interaction potential is obviously 
not limited to drugs used only for illicit purposes : From the reported 
interaction effects, the concurrent use of marihuana with licit drugs 
could conceivably result in an increased toxicity, a diminished thera- 
peutic effectiveness or, even, an enhanced therapeutic effectiveness. 

Another report of a potentially significant drug interaction centers 
on the delta-9-THC blockade of the morphine-abstinence syndrome. 
If this effect is confirmed, then the characteristics and consequences 
of the interaction should be defined further, particularly with refer- 
ence to other drugs known to block the opiate-abstinence syndrome. 

The pharmacological studies included in the present Marihuana 
and Health report reveal the toxic influence of marihuana on pre- 
existing pathological states (62) : Thus, the clinical description of 
the adverse effect of smoking marihuana on cardiac function in 
patients with coronary artery disease is a significant contribution 
toward a more comprehensive picture of the toxicity of cannabis. 
There are also reports of animal data indicating that the use of mari- 
huana may adversely affect the control of seizures. This interpretation 
is based on several observations of marihuana's central-nervous-system 
excitatory properties and on the hyperexcitability following with- 
drawal from repeated delta-9-THC treatment. These potentially 
unfavorable interactions with epilepsy may be independent of the 
anticonvulsant properties of marihuana, as is the case with some 
antiepileptic drugs, such as phenobarbital. 

The Report (62) contains descriptions of two pharmacological 
effects that have definite clinical potential : The decrease in intraocular 
pressure and the anticonvulsant activity, both of which are described 
in sufficient detail to warrant serious consideration of their therapeut ic 
application. Furthermore, the quantitative evaluation of the relative 
anticonvulsant and neurotoxic activity of several cnnnabinoids has 
demonstrated that a potentially useful therapeutic effect of cannabi- 
diol is at least partially separable from the motor toxicity of mari- 
huana, a finding which is further supported by the report of 
cannabidioPs complete lack of psychotoxicity in humans. A compar- 
able pharmacological selectivity for other cannabinoid effects deemed 
potentially valuable clinically is thus a distinct possibility. Finally, 
the introduction of numerous synthetic cnnnabinoids presents an 
oppoitunitv to search for the most appropriate agent for any given 
desired effect. 

TOXICOLOGIC A L EFFECTS 

Investigators have continued to evaluate the toxicity associated with 
chronic exposure to the cannabinoids using various routes of adminis- 
tration and several different species. Experiments have been of two 
basic types: those designed to study lethal effects produced by the 
chronic administration of massive doses, and others designed to study 
sublethal toxicitv produced bv relativelv low doses, such as those 
commonly used by humnns. The chronic low-dose work now includes 
rat studies of toxicity following smoke inhalation (71) : The daily 
doses given to 1-. 5- and 23-day exposed animals were analogous to 



37 

those taken by humans, and the results indicate that inhalation of 
delta-9-tetrahydrocannabinol (delta-9-THC) can produce the char- 
acteristic marihuana central-nervous-system (CNS) toxic effects 
(depression and excitation) elicited by other routes of administration. 
These effects, like those associated with other routes of administration, 
appeared in the absence of any pathological changes, and tolerance 
ultimately developed to most of them. In a study of the inhalation 
toxicity of Turkish marihuana (high in cannabidiol and cannabi- 
chromene and low in delta-9-THC content) rats were daily exposed 
to smoke 5 days per week for 25 days (72). This treatment resulted in 
various manifestations of CXS depression and in a dose-related lethal 
effect — respiratory arrest; such results demonstrate that cannabidiol 
(CBD) and cannabichromene (CBC) can contribute to the toxicity 
of marihuana. 

Massive oral doses of delta-9-THC or crude marihuana extract 
administered to rats daily for 28 to 91 days have been used to deter- 
mine toxic neurochemical effects (59) : After 28 days of treatment, 
significant decreases were observed in total brain protein, ribonucleic 
acid (RXA) and acetylcholinesterase activity. These neurochemical 
changes in rats coincided with the appearance of the CXS stimulation 
(fighting behavior and convulsions) characteristic of chronic mari- 
huana treatment, and, like neurotoxicity, were partially reversed by 
91 days of continued administration. 

In a study similar to that described immediately above, neurochem- 
ical changes were evaluated in rats treated for as long as 180 days; in 
this instance 1 , however, the doses were relatively low — 2, 10 or 50 
mg/kg/day orally (60). The two lower doses of delta-9-THC were 
again analogous to the drug content of the marihuana and hashish 
consumed by humans. (This work is the counterpart of a low-dose, 
chronic-toxicity study (74) referred to in the 1974 Marihuana and 
Health report (62). Neurochemical analyses of four areas of the brain 
(frontal cortex, parietal cortex, subcortical regions and cerebellum) 
were made at various times after the initiation of chronic treatment 
and generally showed neurochemical changes comparable to those 
produced in the massive-dose study described above. In the lower-dose 
study, however, changes required longer periods of treatment to appear 
and varied in the different areas of the brain. Some of the behavioral 
and neurochemical changes were sex-linked, and several occurred after 
the development of tolerance to the behavioral effects. Furthermore, 
a few of the neurochemical alterations were reversible, even after a 
30-day recovery period. 

Neurotoxicity and EEG, effects of chronic oral treatment of rats 
and rhesus monkeys have also been described (79, 80). In rats acute 
treatment with 10 mg/kg delta-9-THO increased the frequency of 
surgically induced polyspike activity, while chronic treatment resulted 
in subcortical spike bursts with concomitant seizures. In the rhesus 
monkey chronically treated with crude marihuana extract equivalent 
to 12.5 mg/kg delta-9-THC or more, the neurotoxic manifestations 
always preceded and outlasted the effects on the EEG, and tolerance 
developed more rapidly to the EEG effects than to the neurotoxicity. 
The results suggest that the neurotoxic effects become manifest at 
lower doses than the characteristic EEG effects, findings similar to 
those previously reported in humans. 



38 

Monkeys treated intravenously (i.v.) with delta-9-THC exhibited, 
at the injection site, such toxic reactions as edema, necrosis, ulceration 
and fibrosis (83). In order to elaborate the local toxicity findings, the 
drug was chronically administered subcutaneously (s.c.) to rabbits in 
doses ranging from 15.9 to 153.4 mg/kg/day. The dermal responses, 
which were generally dose-related, included erythema, edema, ulcera- 
tion and nodule formation. These results illustrate that the use of 
marihuana i.v. may be accompanied by local toxic reactions. The 
chronically treated animals displayed dose-related decreases in body 
and liver weights, in glycogen content of the liver, and in blood sugar 
and alkaline phosphatase activity; serum potassium concentration was 
elevated. As in other chronic toxicity studies from this group, no 
pathological tissue effects — other than those at the injection site — 
were discernible. 

A study of the influence of different routes of administration and 
vehicles on the lethal dose 50 (LD50) values of delta-9-THC has also 
been made (73). The oral LD50 for delta-9-THO in an aqueous emul- 
sion of sesame oil and polysorbate 80 was similar to that obtained 
with a pure sesame-oil vehicle, indicating that the composition of the 
emulsion did not affect the LD50. Furthermore, the i.v. LD50 for the 
same aqueous formulation was essentially identical to the inhalation 
LDr>0. In general, the results established the validity of the i.v. route 
of administration in the investigation of the pharmacology and toxi- 
cology of marihuana-like substances. 

The continuing interest in the carcinogenic potential of marihuana 
smoke has brought forth a report that marihuana tar painted on 
mouse skin produced a variety of effects on squamous cells, including 
metaplasia of sebaceous glands (20). This good correlation with the 
established carcinogenicity of tobacco smoke led the investigators to 
conclude that cannabis smoke will also be carcinogenic, a conclusion 
which is supported by bioassays of marihuana tar on mouse skin. Both 
tumorgenicity and tumor-promoting activity were revealed although 
at levels significantly lower than those resulting from tobacco smoke 
(41) . This contrasts with in vitro observations on human lung explants 
which suggest that cannabis smoke may be more carcinogenic than 
tobacco smoke (91). 

In another investigation, marihuana smoke produced a dose- 
dependent depression of the bactericidal activity of pulmonary alveo- 
lar macrophages: the effect was related to a water-soluble constituent 
in the smoke rather than to delta-9-THC (23). It is possible that the 
toxicity of marihuana smoke to the alveolar macrophage may impair 
the ability of this cell to function in the host-defense mechanism of 
the lung. 

Numerous reports have appeared describing the effects of delta-9- 
TIIC on the endocrines. The main thrust of research in this area has 
aimed at pituitary and gonadal hormones. (See Appendix G "Human 
Effects" for a detailed review of the latter.) One of the previously 
reported effects of heavy marihuana use in humans was gynecomastia 
(37). This effect has now been produced in rats given 1 mg/kg delta- 
9-TITC s.c. for two to three weeks (38). In a related study, delta-9- 
THC in male rates increased pituitary weight, total pituitary prolactin 
and the concentration of prolactin in serum (24), but in a similar 



39 

study, delta-9-THC decreased, rather than increased, serum prolactin 
concentrations (57). The discrepancy in these results may be due in 
part to differences in dosage: The effect in the former study was 
obtained at 16 mg/kg. In humans, marihuana use has had no apparent 
effect on serum prolactin. The gynecomastia described above was asso- 
ciated with normal serum hormone values, wmile another group of 
chronic marihuana users was also normal (56) . 

Kesearoh into the effect of delta-9-THC on other pituitary hormones 
has indicated that in rats delta-9-THC in doses of 5 to 20 mg/kg 
inhibited growth hormone and stimulated adrenocorticotropic hor- 
mone secretion ; daily administration of 20 mg/kg for 20 days did not 
produce tolerance to these effects (55) . The findings suggest that delta- 
9-THC acts as a stress stimulus of the hypothalamicpituitary axis. A 
similar response to delta-9-THC in the mouse was evidenced by an 
increase in corticosterone concentration in plasma (69), although tol- 
erance to the effect on steroid secretion rapidly developed in this 
species. The work of one group of investigators has shown an 
inverse relationship between plasma corticosterone and the amount of 
5-hydroxytryptamine in whole brain. A positive correlation between 
the steroid value and aggressive behavior in ovariectomized rats fol- 
lowing chronic cannabis treatment was found (66). Aggressiveness 
was abolished by estrogen treatment, suggesting that previously 
described sex differences in response to cannabis may, in part, have 
been due to female variability during different phases of the estrus 
cycle. 

The inhibitory effect of delta-9-THC on the secretion of growth 
hormone also manifested itself in prepuberal male rats (IT), but in 
adult female rats high doses of the drug (50 mg/kg) elevated serum 
growth hormone values (28). In a study of male mice chronically 
treated with delta-9-THC, growth was depressed in a way similar to 
that seen in estradiol treated animals, suggesting that delta-9-THC 
can exert an estrogen-like effect (78) . 

PHARMACOLOGICAL EFFECTS 

The similarities in psychological actions between the liqueur 
absinthe and cannabis have led to a molecular structural comparison 
of their active principles, thujone and tetrahydrocannabinol (26). 
Because the substances have a similar molecular geometry and similar 
functional groups, they may exert their psychic effects by interacting 
with a common receptor in the CNS. The receptor should have a bind- 
ing site for oxygen, a planar region for the allyl group and pockets, 
or cavities, for fitting with alkyl and hydrogen groups that are com- 
mon to both drugs. The importance of the phenolic hydroxy 1 group in 
tetrahydrocannabinols in eliciting delta-9-THC-like activity in ani- 
mals has also been established (86) . 

Studies of the effects of delta-9-THC on sleep-wakef ulness patterns 
referred to in the 1974 Marihuana and Health report (62) have been 
expanded to include the male squirrel monkey whose patterns are simi- 
lar to those of the human (1). Chronic treatment reduced slow- wave 
sleep time, which failed to return to normal, even after a 30-day 
recovery period. In addition to this change in sleep pattern, the time 



40 

spent in Stage 1, or drowsy sleep was increased in treated animals and 
this change also persisted throughout the recovery period. 

The analgesic activity of delta-9-THC has now been described in 
the dog, as well as in the rat, mouse and rabbit (54). Tolerance, which 
has been found to develop to such other effects in the dog as ataxia and 
sedation, also developed to the analgesic effect. Two cannabinoid-free 
extracts (an aqueous extract and a volatile oil) of marihuana also 
were found to elicit analgesia in mice. The analgesic potency of the 
extracts was much lower than that of delta-9-THC, but the nature of 
the analgesic material and its interaction with delta-9-THC are still 
unknown. 

Many cannabinoids, in addition to delta-9- and delta -8-THC, are 
known to be anticonvulsants: These include cannabinol (CBX), 
dimethvlheptvlpvran (DMHP) and some of its isomers ; 11-hvdroxv- 
delta-9-THCM46) ; 8-alpha, ll-dihydroxy-delta-9-THC (45); and 
some new benzopyrans (TO). Moreover, the activity of CBD has been 
confirmed and the compound subjected to a variety of seizure tests 
which have demonstrated that in its anticonvulsant properties the drug 
more closely resembles diphenylhvdantoin (DPH) than does delta-9- 
THC (44, 49, 85). The interaction of CBD with other anticonvulsant 
drugs has also been described in studies that generally show that, in a 
maximal elect roshock test in mice, CBD clearly enhances the potcncv 
of delta-9-THC, DPH and phenobarbital (PB). The determination 
of the protective indices (toxic dose/anticonvulsant dose) of several 
cannabinoids in mice indicates that motor toxicity is a separable effect 
from anticonvulsant activity (46) ; for example, compared witli delta- 
9-THC, DMHP is relatively more toxic and CBD significantly less 
toxic. Furthermore, the separation of toxicity from anticonvulsant 
activity is dramatically illustrated by the report that massive i.v. doses 
of CBD in humans do not produce either the marihuana-like psycho- 
toxicity or tachycardia (68). 

In rats and mice subjected to a maximal electroshock test, tolerance 
to the protective effect of delta-9-THC and CBD rapidly developed 
(46, 47), but a similar response to repeated treatment was associated 
witli DPII and PB (47); in addition, tolerance to delta-9-THC or 
CBD involved cross-tolerance to DPH and PB (47). Tolerance has 
also been described for the antiseizure activity of delta-9-THC in the 
gerbil, but in this case it did not develop to the neurotoxic effects (82). 
It should be noted, however, that a study of the influence of repealed 
daily drug treatment on the results of several anticonvulsant tests 
indicates that tolerance does not develop to all the anticonvulsant 
properties of the cannabinoids (48). In fact, in some tests anticon- 
vulsant activity increased, rather than decreased, with repeated treat- 
ment. Similar results were obtained with DPH but not with PB. The 
evidence suggests that the tolerance observed is not a dispositional but 
a functional adaptation. For example, in one study tolerance to pro- 
tection agaklSt a maximal electroshock' developed concurrent with an 
accumulal ion of cannabinoids in the ( \S and increased sensitivity to 
cannabinoids in certain anticonvulsant tests, while no change occurred 
in plasma delta-9-TJ EC concentration or in barbiturate sleep time (48). 

Previous reports mentioned descriptions of some excitatory prop- 
ert ies of delta-9-Tl !( '. especially in conjunct ion with toxicity produced 



41 

by chronic, high-dose treatment. Withdrawal from repeated treatment 
with anticonvulsant doses of delta-9-THC also resulted in CNS hyper- 
excitability, as measured by a decrease in the 6-Hz-electroshock thresh- 
old test for minimal seizures (49, 50) ; no such withdrawal increase 
manifested itself in the case of CBD or DPH. On the other hand, 
withdrawal hyperexcitability to delta-9-THC could not be demon- 
strated when pentylenetetrazol (PTZ) was used to elicit minimal 
seizures (11). Following low-dose, i.v. administration, convulsant 
effects of delta-9-THC have been observed in a special strain of rabbits 
(19). Furthermore. deHa-9-THC administered i.v. to the photosensi- 
tive baboon Papio papio resulted in an epileptiform EEG response, 
3/sec rhythmic spikes and waves (63) ; no doses were anticonvulsant 
against the photically elicited myoclonic activity, but high doses (1-5 
mg/kg) enhanced seizure responses in some cases. 

In the area of cannabinoid hypothermic activity, one recent study 
compared several cannabinoid preparations with chlorpromazine in 
mice (58) and ranked them in order of decreasing potency as follows : 
chlorpromazine. marihuana extract, distillate. DMHP. delta-8- and 
delta-9-THC. Tolerance to the effects of both delta-9-THC and chlor- 
promazine rapidly developed, although more rapidly to the former 
drug. Antipyretic activity for delta-9-THC, suggested by previous 
reports, have now been confirmed in mice (16). Additionally, with 
respect to the mechanism which lowers body temperature, the results 
from direct and indirect calorimetry measurements suggest that delta- 
9-THC-induced hypothermia is associated with both a decrease in heat 
production and an increase in heat loss (4, 88). In brain, some investi- 
gators have found a decreased tissue metabolic rate following in vivo 
drug administration and a subsequent tolerance (64). Such an effect 
on metabolic rate could be mediated by either a direct or indirect action 
of the cannabinoids: A direct effect of several cannabinoids on tissue 
oxygen consumption in vitro has been described by another research 
group (14) who reported that the cannabinoids depress the oxygen 
consumption of homogenates of liver, heart, brain and skeletal muscle. 
Moreover, mitochondrial preparations from the latter two tissues were 
studied further and their metabolic rates were also depressed. The 
dose-response data from the oxygen consumption research indicate 
that hypothermic doses of delta-9-THC yield tissue-drug concentra- 
tions sufficient to depress metabolic rate directly. 

Recent research into the cardiovascular effects of marihuana has 
yielded a number of studies on various facets of this subject (cf. 15). 
For example, it has been found that in rats tolerance does not develop 
to the bradycardia commonly associated with chronic marihuana treat- 
ment (53). In addition, the effect of delta-9-THC on cardiac function 
has been described in pentobarbital-anesthetized dogs with an elec- 
trically maintained constant heart rate (9). In this study, the drug 
decreased aortic blood pressure, cardiac output, left ventricular peak 
pressure and left ventricular end-diastolic pressure, but the contractil- 
ity index was not affected. The decrease in cardiac output could be 
restored to normal by elevating left ventricular end-diastolic pressure 
with an expansion of plasma volume. In dogs with a maintained con- 
stant cardiac output, delta-9-THC decreased blood pressure and total 
peripheral resistance, but increased intravascular blood volume. These 

67-062—76 — —4 



42 

results indicate that the delta-9-THC induced decrease in cardiac out- 
put in the presence of constant cardiac rate is due to a decreased venous 
return, rather than to a decrease in myocardial function. 

In a study using spinal preparations, delta-9-THC exerted no cardio- 
vascular effects; hence, the role of the CNS in mediating delta-9- 
THC's effects on heart rate and blood pressure was investigated in cats 
anesthetized with chloralose (87). Spinal transection (C1-C2) abol- 
ished the drug-induced bradycardia and hypotension. The delta-9- 
THC-caused bradycardia was also blocked by the surgical removal of 
tone to the heart, but neither heart-rate nor blood-pressure effects were 
modified by bilateral vagotomy. Sympathetic outflow in the inferior 
cardiac nerve decreased after delta-9-THC administration although 
peripheral sympathetic functions were unaffected; thus, the cardio- 
vascular effects of delta-9-THC appear to be due to a CNS action which 
results in a decrease in sympathetic tone. 

Other investigators have examined the relationship between the 
sympathetic nervous system and delta-9-THC's cardiac effects in terms 
of changes in the uptake of noradrenaline by the heart and have found 
that delta-9-THC, like cocaine, can decrease in a dose-related manner 
the uptake of noradrenaline by the isolated, perfused rat heart, al- 
though cocaine appears to be about ten times more potent than delta- 
9-THO (32). The significance of such effects is not yet clear, but of 
great interest is the report that smoking marihuana can adversely 
affect cardiac function in patients with angina pectoris (3). In these 
patients, smoking one marihuana cigarette containing 19.8 mg delta- 
9-THC decreased exercise performance significantly more than smok- 
ing one placebo cigarette. 

The cannabinoids' ability to decrease intraocular pressure is still 
inciting investigation and several congeners of delta-9-THC, admin- 
istered either systemically or topically, have now been tested. These 
are listed in order of decreasing efficacy: ll-hydroxv-delta-9-THC; 
delta-9-THC; 8 alpha, ll-dihydroxy-delta-9-THC; SP111A; other 
derivatives (33). Delta-9-THC can decrease the pressure in the rabbit 
eye by 25% and increase outflow capacity by 70% and the role of the 
sympathetic nervous system in mediating these effects has been estab- 
lished (34, 35, 36). The alpha-response is an enhanced total outflow 
facility and the beta-response is a vasodilatation of the efferent ves- 
sels from the anterior uvea, thereby causing a decrease in the forma- 
tion of aqueous humor. Part of delta-9-THC's effect on intraocular 
pressure appears to be mediated through these actions on sympathetic 
receptors ; but most arises from a central effect. 

The influence of cannabinoids on biogenic amines continues to be a 
focal point for studies of their mechanism of action. In a rat study of 
repeated delta-9-THC treatment on brain metabolism of 5-hydroxy- 
tryptamine (5-HT) and norepinephrine (NE) , the products of metab- 
olism were isolated from whole brain following the intracisternal 
administration of radiolabeled 5-HT or NE (40). Chronic treatment 
yielded a decrease in the metabolism of 5-HT but an increase in that 
of NE. In another study in the rat, the effect of hypothermic doses of 
delta-9-THC on the metabolism of 5-HT and NE in the hypothalamus 
and brainstem was reported (89) , and these results show that there a re 
no changes in either the amount or the turnover of these amines in the 



43 

two parts of the brain investigated. Several cannabinoids have been 
examined for their effect on the uptake of XE, 5-HT, dopamine (DA) 
and gamma-aminobutyric acid (GAB A) by synaptosomes derived 
from various regions of the rat brain (6). The findings indicate that 
cannabinoids can inhibit the uptake of NE, 5-HT and GABA by 
hypothalamic synaptosomes ; in addition, a discussion of the structural 
requirement for these effects is included. Delta-9-THC can also aug- 
ment the release of XE from the isolated rat vas deferens (32), an 
observation which has led to the suggestion that the release of trans- 
mitter from peripheral stores may, in part, account for the hypotensive 
activity of delta-9-THC. Delta-9-THC can decrease the uptake of DA 
by crude striatal synaptosomal preparations (42) ; however, ampheta- 
mine is more potent in this regard. Delta-9-THC also appears to alter 
the intraneuronal disposition of DA without any effect on its metabo- 
lism (65). It is possible that these effects are related to delta-9-THC's 
known interaction with amphetamine. 

Studies of the mechanism of action of delta-9-THC have been 
expanded to include its effect on cyclic adenosine. 3'.5'-monophos- 
phate (cyclic AMP), and investigators have found that low doses of 
delta-9-THC (0.1-1.0 mg/kg intraperitoneally) cause a 50-160% 
increase in brain cyclic AMP, whereas higher doses (2.0-10 mg/kg) 
depress cyclic AMP 30-60% (27). This biphasic response apparently 
correlates with other previously reported biphasic responses in bio- 
genic amines, temperature regulation and behavior. 

The influence of tetrahydrocannabinols on brain acetylcholine con- 
tent has also been investigated (5). The intravenous administration 
of 5 mg/kg delta-9- or delta-8-THC was found to decrease brain 
acetylcholine content, while ll-hydroxy-delta-9-THC, a metabolite, 
was ineffective. Delta-8-THC did not appreciably alter either acetyl- 
cholinesterase or choline acetyltransf erase. The decrease in acetyl- 
choline was not observed in rats treated with 6 mg/kg intraperitoneally 
(90). In contrast to the results described above for acute experiments, 
chronic oral cannabinoid treatment produced a decrease in brain 
acetylcholinesterase activity, as well as a decrease in total protein and 
RNA (59) : however, no changes were observed in brain lipid, glyco- 
lipid or cholesterol concentration. In the chronic study, the neuro- 
chemical changes coincided with the onset of neurotoxicity; further- 
more, both were partially reversed during continued drug treatment. 
The mechanism of some of the anticholinergic effects of the canna- 
binoids remains to be elucidated. 

The relationships between cannabis and prostaglandins have been 
studied further and it has been confirmed that cannabinoids inhibit 
the formation of prostaglandins PGEl and PGE2 but they also stim- 
ulate PGF production (22). In another study, eugenol. a minor vola- 
tile constituent of cannabis, was found to be a more active inhibitor 
of PGEl synthesis than was delta-9-THC. This observation, com- 
bined with a demonstration of pharmacological activity in the essen- 
tial oil fraction (76), indicates a need to consider the role of these 
substances in the pharmacology of cannabis. The release of PG-like 
substances by delta-9-THC from both rabbit kidney and guinea-pig 
lung has been reported (52) : These substances produced renal vaso- 
dilation and pulmonary vasoconstriction, responses which were blocked 



44 

by aspirin. The former effect may account for the diuretic property 
ascribed to delta-9-THC, while ihe delta-9-THC-caused release of 
PG-like material may be related to the increase in PG synthesis re- 
ferred to above (22). 

An examination of the influence of acute and chronic delta-9-THC 
treatment on the lipids of rat brain subcellular fractions has revealed 
the following effects : Acutely, the lipid content of the mitochondrial; 
synaptosomal and myelin fractions decreased, but in the microsomal 
fraction all major lipid components increased; chronically, these 
changes tended to return to normal (75). Other reports have noted 
a lysis of rat liver lysosomes in vitro bv high concentrations of delta- 
9-THC (8), and the uptake of delta-9-THC in vivo by the lysosomes 

Numerous interaction studies of marihuana constituents have been 
undertaken since the last report and the interaction between canna- 
binoids, particularly between delta-9-THC and CBD, has received a 
great deal of attention. CBD'S ability to antagonize some of the be- 
havioral effects of delta-9-THC has been established and studies have 
been extended to the investigation of other effects. In one such study, 
prior treatment with CBD blocked the delta-9-THC induced catatonia, 
corneal areflexia and aggresiveness in KEM sleep-deprived rats (51). 
In addition, CBD potentiated the delta-9-THC analgesic effect and 
impairment of rope climbing. In another study, pretreatment with 
apparently inactive doses of CBD reduced the depressant effectsof 
delta-9-THC on body temperature, on heart rate and on respiration 
(7). CBD also reduced the depressant effects of delta-9-THC on 
variable-interval and fixed-interval schedules of food reinforced oper- 
ant behavior (25). In these tests, high doses of CBD did affect these 
behavioral parameters, suggesting that CBD can function as a partial 
agonist. A comparison of the interaction of CBD and CBN with delta- 
9-THC showed that CBD intensified delta-9-THC's effects on animal 
motility, on food and water intake, on body temperature, on catalepsy, 
and on hexobarbital sleep time (30). CBN, in general did not alter 
the activity of delta-9-THC, except in the barbiturate sleep-time test. 
In this case, CBN, in contrast to CBD, blocked the delta-9-THC 
prolongation of hexobarbital sleep time, thus corroborating an earlier 
report of CBN antagonism. The evidence presented suggests that CBD 
heightens the effects of delta-9-TIIC by a metabolic interaction at the 
level of the hepatic drug-metabolizing enzymes ; on the other hand, the 
observed antagonism between CBN and delta-9-THC on sleep time 
appears to be a central interaction (29). The ability of CBD to poten- 
tiate the anticonvulsant activity of delta-9-THC was described above 
(85). An in vitro potentiation has also been reported (2). Both delta- 
9-TIIC and CBD were found to depress intestinal motility, but delta- 
9-TIIC was more potent. Inactive doses of CBD increased the depres- 
sant effect of delta-9-THC, demonstrating that potentiation was not 
necessarily mediated by a CBD blockade of delta-9-Tl EC's metabolism. 
The interaction of CBN with depressant, excitatory and peripheral 
effects of delta-9-THC has also been described (81) : Inactive doses of 
CBN appeared to enhance the depressant effects and slightly inhibit 
excitatory effects, while having no effect on a peripheral response to 
delta-9-THC. 



45 

Additional studies have focused primarily on the interaction of can- 
nabinoids with other drugs. Acutely, delta-8-THC, in a dose-related 
manner, prolonged alcohol sleep time, but tolerance developed to this 
interaction with repeated cannabinoid exposure (31). The enhanced 
sleep time produced acutely cannot be attributed to an altered rate of 
alcohol metabolism (31). The possibility that some of the effects of 
delta-9-THC are mediated by an action on chemical transmitters has 
been pursued by measuring the cannabinoid's influence on the LDoOs 
of certain drugs. It was found to intensify the toxicity of some cholin- 
ergic drugs but to attenuate the toxicity of others: the toxicity of 
adrenergic drugs was significantly reduced by the pretreatment with 
delta-9-THC and, finally, delta-9-THC increased the toxicity of a 
5-HT-blocking drug (77). 

The interaction studies of cannabinoids and barbiturates have been 
expanded to include ether anesthesia (13, 61). Cannabis extract pro- 
longed the duration of both barbiturate and ether anesthesia. How- 
ever, after repeated treatment, tolerance developed to the interaction 
with ether but not to that with pentobarbital. CBX also prolonged the 
duration of ether anesthesia, but CBD tended to antagonize ether. The 
investigators suggested that the failure of others to observe any such 
effect on ether anesthesia may have been the consequence of the variable 
cannabinoid composition of cannabis extracts. 

A study of the interaction of delta-9-THC pretreatment with 
d-amphetamine in aggregated mice, indicated that cannabinoid pre- 
treatment can potentiate motor activity and lethality without affectina' 
hyperthermia ('21): these effects were associated with a decrease in 
the amount o,f amphetamine in the brain. The influence of a combined 
treatment of detla-O-THC and methamphetamine on the EEG and on 
behavior has been described by other investigators vim reported meth- 
amphetamine reversed the delta-9-THC effects o nthe EEG. but the 
combination of drugs produced some striking behavioral disturbances, 
which appeared to be a potentiation of methamphetamine toxicity 
( 18) . An interaction between delta-9-THC and a naloxone-precipitated 
abstinence in morphine-dependent rats appears to exist for a single 
delta-9-THC pretreatment can block in a dose-related manner the 
naloxone-induced abstinence signs. Pretreatment with 10 mg/kg CBD 
failed to produce any such effect (39) . 

It should be noted that two comprehensive reviews (67, 84) on the 
general subject of the pharmacology of marihuana have appeared since 
the 1974 Marihuana and Health report (62) . 



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41. Hoffman, D.. Brunnemann, W. D., Gori. G. B. and TYynder. E. L. On the 
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48 

43. Irvin, J. E. and Mellors, A. Delta-9-tetrahydrocannabinol-uptake by rat 
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9-tetrahydrocannabinol and its 11-hydroxy and S-alpha-11-dihydroxy metabo- 
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49 

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67. Paton, W. D. M. Pharmacology of marijuana. "Annual Reviews of Pharma- 
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68. Perez-Reyes, M., Timmons, M. D., Davis, K. H. and Wall. M. E. A compari- 
son of the pharmacological activity of delta-9-tetrahydrocannabinol and its mono- 
hydroxylated metabolites in man. "Experientia," 29:1368-1369 (1973). 

69. Pertwee, R. G. Tolerance to the effect of delta-1-tetrahydrocannabinol on 
corticosterone levels in mouse plasma produced by repeated administration of 
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and Applied Pharmacology." 28 : 18-27 (1974) . 

74. Rosenkrantz, H., Sprague. R. A.. Fleischman, R. W. and Braude, M. C. 
Oral delta-9-tetrahydrocannabinol toxicity in rats treated for periods of up to 
months. "Toxicology and Applied Pharmacology," 32:399-417 (1975). 

75. Sarkar, C. and Ghosh, J. J. Effect of delta-9-tetrahydrocannabinol adminis- 
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76. Segelman, A. B., Sofia. R. D., Segelman, F. P., Harakal, J. J. and Knobloch, 
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77. Sofia, R. D. and Knobloch, L. C. Influences of acute pretreatment with delta- 
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78. Solomon, J. and Shattuck, D. X. Marihuana and sex. "New England Journal 
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79. Stadnicki, S. W., Schaeppi, U., Rosenkrantz, H. and Braude, M. C. Delta-9- 
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50 

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at the International Conference on the Pharmacology of Cannabis. Savannah, 
December, 1974. 



CHAPTER 4 

Preclinical Effects: Unlearned Behavior 

As the studies reviewed in the four previous Marihuana and Health 
reports (44, 45. 46, 47) have shown, the cannabinoids produce a variety 
of effects on unlearned behavior in different animal species. The litera- 
ture pertaining to cannabis and unlearned behavior is now quite volu- 
minous. Consequently, this appendix focuses primarily on the relevant 
literature which has appeared since the last report, although some 
attempt is made to consider this literature in light of previous findings. 
Furthermore, for the sake of exposition the appendix is organized 
around four categories of unlearned behavior: gross behavior; activity 
and exploration: consummatory behavior; and aggressive behavior. 

GROSS BEHAVIOR 

Much of the early preclinical research with canabinoids investi- 
gated the effects of these drugs on the gross behavior of a wide range 
of animal species. As has been discussed in previous Marihuana and 
Health reports and recent reviews of the animal literature (e.g., 53) 
a variety of gross behavioral changes are induced in animals by the 
cannabinoids. Included among these effects are ; catalepsy, ataxia, ab- 
normal body postures, hypersensitivity, and hyperactivity. Subsequent 
to this earlier work on gross behavioral changes, much of the preclini- 
cal work with cannabinoids pertained to learned rather than un- 
learned behavior. Most recently, however, there has been a renewal of 
interest in the gross behavioral changes induced in animals by canna- 
binoids. The primary reason for this has been the recognition that 
complex pharmacological interactions may occur among the canna- 
binoids. 

The majority of cannabinoids research on unlearned behavior has 
used delta-9-THC or delta-8-THC since these particular cannabinoids 
have been established as the major active components of cannabis 
samples (49). However, several researchers reported that the phar- 
macological activity of cannabis samples was not always entirely ex- 
plained by the tetrahydrocannabinol content of the samples (7, 36. 55). 
This led to the suggestion that interactions between THC and other 
cannabinoid constituents of cannabis, namely cannabidiol (CBD) and 
cannabinol (CBX), mav be important. This suggestion was supported 
bv findings that CBD 'inhibits the metabolism of delta-9-THC (25, 
35, 42). < 

Experiments dealing with interactions of cannabinoids on gross 
unlearned behavior are still few in number. However, those inter- 
actions which have been observed appear, at this time, to be complex 
and are not always consistent among experiments. For example, in 

(51) 



testing the effects of cannabinoids on catalepsy in rodents, investi- 
gators have found CBD and CBN administered alone to be either 
ictive (37, 61) or inactive (24). Moreover, when administered in com- 
bination with delta-9-THC, CBN has been reported either to have no 
effect on catalepsy (24) or to potentiate delta-9-THC induced cata- 
lepsy (61). Finally, CBD in combination with delta-9-THC has been 
•eported to prolong (24) or to enhance (37) catalepsy induced bv 
ielta-9-THC. 

The interactions between the cannabinoids on drug-induced loss of 
the righting reflex (anesthesia, sleeping-time) seem to be particularly 
complex (14, 15, 25, 37, 41, 43, 61). For example, CBN antagonizes 
ielta-9-THC effects on pentobarbitone- (41) and hexobarbitone- (25) 
induced loss of the righting reflex but potentiates delta-9-THC-ether 
affects on the same unlearned response system in the same animal 
species (43). The complexity of these and other interactions (14) will 
most likely be better understood with additional research — especially 
research which can distinguish between drug interactions involving 
CNS activity and those involving cannabinoid-induced changes in 
tetrahydrocannabinol metabolism. 

As would be expected, THC interacts with drugs other than the 
cannabinoids to affect unlearned gross behavior. Recent experiments 
have shown that delta-8-THC potentiates the loss of righting reflex 
induced in rats by alcohol (27) while delta-9-THC potentiates some, 
and antagonizes other, amphetamine-induced postural and activity 
behaviors in rats (30) and rabbits (16). 

ACTIVITY AND EXPLORATION* 

Based on the reseai-eh available at the time, the 1974 Marihuana 
and Health report (47) concluded that "cannabinoids generally sup- 
press the spontaneous motor activity and exploration of animals, 
although findings regarding these effects are limited, as always, by 
drug route, time-effect, and drug-response considerations" (20, 26). 
The suppression effect of delta-9-THC on spontaneous motor activity 
has been confirmed by two recent studies (6, 56). Tn one of these (6), 
oral doses of delta-9-THC ranging from 1.25 mg/kg to 40.0 mg/kg 
were administered acutely to mice. The lowest drug dose produced a 
significant increase in activity while the remaining drug doses pro- 
duced a dose-dependent suppression of activity. Other mice were used 
to investigate tolerance to the suppressive effects of 40.0 mg/kg of 
delta-9-TIIC (p.o.) on spontaneous activity. Complete tolerance 
developed after one dose and had a duration of less than four days. 

Another aspect of this latter study ((>) deserves mention. Specif- 
ically, the activity of mice that had been previously habituated to 
the experimental apparatus was not suppressed by a 40.0 mg/kg dose 
of delta-9-THC. This finding is in accord with other research (17, 19) 
which shows that prior habituation to an experimental situation can 
alter the effects of TTTC on motor activitv in animals. 

Delta-9-THC doses of 30.0, 60.0 and 120.0 mg/kg were administered 
subcutaneously to pregnant rats on the fourth day of gestation (00). 
T< was found that delta-9-THC produced an increase in abnormal 
pregnancies but that it had no significant etVect on the locomotor act iv- 



53 

ity of the offspring. This latter finding is at odds with a previous 
experiment (7) in which effects were observed on the unlearned 
behavior of offspring from pregnant rats that had been administered 
delta-9-THC subcutaneously during the tenth to twelfth days of 
gestation. Additional research is needed to determine whether delta- 
9-THC has a direct action on the developing fetus which becomes 
manifest in the unlearned behavior of offspring. 

The spontaneous activity of rats was additionally used to study the 
drug interaction between delta-9-THC and phencyclidine (56). It 
was found that an increase in activity produced by 5.0 mg/kg intra- 
peritoneal injections of phencyclidine was antagonized by oral doses 
of delta-9-THC, ranging from 2.5 to 10.0 mg/kg, in a dose-related 
manner. 

Exploratory behavior and performance on simple unlearned motor 
tasks have also been used recently to study the interactions of delta- 
9-THC with other cannabinoids. First of all, it has now been reported 
that CBD and cannabichromene (CBC), in inhaled doses from 1.0 to 
2.0 mg/kg decreases exploratory behavior of rats in a dose-related 
manner (57) while CBX (10.0* mg/kg; i.p. injection) significantly 
increased exploration-ambulation in rats (61). However, CBD did not 
affect the motor coordination of mice over a wide range of i.p. doses 
(62). In combination with delta-9-THC. both CBD (37) and CBX 
(61) produce a pharmacological interaction on exploratory behavior 
in rats, although delta-9-THC and CBD do not seem to interact to 
affect motor coordination in mice (62). 

CONSUMER BEHAVIOR 

Prior to 1973 delta-8-THC, delta-9-THC, hashish resin, and pyra- 
hexyl were all shown to produce reductions in food and water intake, 
with a consequent weight loss, in animals. Research appearing since 
that time, much of which was reviewed in the fourth Marihuana and 
Health (47) report, has generallv confirmed and extended these find- 
ings for delta-8-THC and delta-9-THC (3. 28, 32. 33, 39, 59, 60). In 
addition, inhaled doses of CBD and CBC have been recently shown to 
reduce the rate of growth in rats and to decrease their food and water 
consumption in a dose-related manner (57) . On the other hand, neither 
CBN nor CBD were found to affect food and water consumption over 
a range of i.p. doses up to 80.0 mg/kg (24). However, in this latter 
study, CBD, but not CBX, was found to enhance the suppressive ef- 
fects on consummatory behavior produced by delta-9-THC. 

The general findings of cannabinoid-induced suppression of con- 
summatory behavior stands in stark contrast to the findings that mari- 
huana or hashish will increase the human appetite for food (1, 31). 
Several possible explanations have been offered to account for this 
discrepancy. Sofia and Barry (60) have suggested that since pure 
delta-9-THC has not been used with humans, the appetite-stimulant 
effect of marihuana might be due to a constituent other than THC. 
The recent findings regarding CBX, CBD and CBC reported above 
(24, 57) seem to make this suggestion less likely. It has also been sug- 
gested that, since most animal studies have not taken continuous meas- 
urements of consummatory behavior, increases in consumption may 



54 

have been overlooked. However, in recent experiments with rats where 
such continuous measures have been taken (32, 60), dose-related delta- 
9-THC decreases in food and water intake have been confirmed. There 
is some evidence (28) to support the contention (22) that the discrep- 
ancy between animal and human consummatory behavior is due to the 
higher cannabinoid doses, relative to body weight, used in animals 
than in humans. Furthermore, the possibility that the discrepancy is 
related to humans' adaptation to a long-term deprivation regimen 
whereas most animals used as either nondeprh^ed or acutely deprived 
has also received empirical support (29). Nevertheless, the discrepancy 
between animal and human experiments is inadequately explained. 
There is, of course, the possibility that the differences are due solely to 
between-species differences. If so, consummatory behavior will stand 
as a rare instance in which animal research with cannabinoids has not 
served reliably as a predictor of cannabinoid effects in humans. 

AGGRESSIVE BEHAVIOR 

If aggression is taken as a uniform behavior of threatening or 
attacking another animal, then conflicting findings regarding the 
effects of cannabinoids on aggressive behavior exist in the literature. 
However, a variety of procedures has been used to study the aggressive 
interactions between animals under the influence of cannabinoids, each 
of which tends to involve a different kind of aggressive behavior. In 
fact, when separated by aggression paradigms, the literature regard- 
ing cannabinoid effects on aggressive behavior is quite consistent. In 
general, the conclusion from both the last Marihuana and Health 
report (47) and a recent extensive review of the cannabis and aggre- 
sion literature in animals (2) is that cannabinoids suppress aggressive- 
ness in nonstressed animals but increase stress-induced aggression. 
T\ T hile one recent study (51) has demonstrated an increase in agression 
following long-term administration of THC to rats which were not 
apparently stressed, the above conclusion applies to the acute cannabi- 
noid experiments on animal aggressiveness which have appeared since 
tlio hist report. For the sake of discussion, the new experiments will be 
divided into categories of stress- induced and nonstress-induced aggres- 
sion, with the latter category being subdivided into isolation-induced 
aggression, competitive aggression and predatory aggression. 

Stress-induced aggression 

As indicated, when stressed animals are put under the influence of 
cannabinoids the usual outcome is an increase in aggressiveness. This 
outcome seems to be independent of the nature of the stressor used. 
Increased aggression under cannabinoids has been reported for such 
stressors as: starvation (13), low temperature (12), REM sleep depri- 
vation (5, 11), withdrawal from morphine (10), septal lesions (21), 
electric shock (9) and most recently, ovariectomy (54). 

Takahashi and Karniol (61) have investigated the interaction 
between CBN and dclta-9-THC with respect to stress-induced aggres- 
sion. Generally, this experiment produced results comparable to a simi- 



00 

lar previous investigation of the interactive effects of CBD and 
delta-9-THC on aggression induced by REM sleep deprivation (37). 
Intraperitoneal injections of 20.0 mg/kg delta-9-THC and 80.0 mg/kg 
CBX induced aggressiveness in the stressed rats. Interestingly, how- 
ever, when the same doses of CBX and delta-9-THC were administered 
together, the amount of aggressiveness was less than that produced by 
delta-9-THC alone (61). 

Isolation-induced aggression 

Several experiments have shown that delta-9-THC and cannabis 
extract will suppress isolation-induced aggression in rats which have 
not also been subjected to stress (e.g., 21, 58). Other studies have 
shown that this cannabinoid-induced suppression of aggression is not 
a result of motor impairment (38) nor does it exhibit tolerance (63). 

The interaction between delta-9-THC and CBD on isolation-induced 
aggression was investigated this year in mice (62). Intraperitoneal 
doses of 2.5 mg/kg delta-9-THC and 40.0 mg/kg CBD individually 
suppressed aggressiveness although the interaction between these two 
cannabinoids was not significant. 

Competitive aggression 

Recent findings are in accord with previous results (34, 52, 64, 65) 
showing that delta-9-THC reduced dominance and social competition 
in animals. For example, Cutler et al. (18) administered cannabis 
resin to mice in i.p. doses ranging from 4.0 to 100.0 mg/kg, then placed 
the mice with unfamiliar partners. These researchers found that the 
drug did not affect nonsocial behavior, social investigation or sexual 
behavior. However, dose-related increases in immobility and flight rela- 
tive to aggression were obtained. 

Ely et al. (23) demonstrated the importance of the existing social 
structure in their examinations of cannabinoid effects on animal ag- 
gression. Doses of 0.5, 2.0 and 20.0 mg/kg of delta-9-THC were intra- 
venously injected into mice whose dominant or subordinate status in 
their colonies was either relatively stable or whose dominance was 
threatened either by a rival or an intruder. In the stable colonies the 
only behavioral change noted was a limited period of reduced activity 
by the dominant males. Dominant mice confronted with a rival ex- 
hibited a reduction of activity and a consequent loss of their dominant 
status. Dominant mice confronted with an intruder made fewer attacks 
on the intruder than nondrugged dominant mice, but their aggressive- 
ness returned to the pre-drug baseline level after 24 hours. 

Dose effects of delta-9-THC on aggressive behaviors of resident and 
intruder rats were examined by Miczek ( 50 ) . This investigator varied 
i.p. dose level from 0.125 to 4.0 mg/kg and found that as the dose was 
increased, attack and threat behaviors of the dominant resident rat 
decreased. Only at the highest dose level of 4.0 mg/kg did delta-9-THC 
interfere with the defensive and submissive behaviors of the intruder. 

Predatory aggression 

Research appearing before the last report (47) supported the con- 
clusion that cannabinoids reduce predatory aggression in nonstressed 



56 

animals (2, 21, 48). Although one study (4) indicated that THC 
could produce muricidal behavior in rats which did not previously 
display such behavior, it was not possible to conclusively determine 
whether stress induced by food deprivation or the administration of 
the cannabinoid over a 40-day period was responsible for this result. 
However, a recent study by Miczek (51) indicates that the long-term 
administration period may have been the crucial factor. This investi- 
gator found that during an administration period of 60 days, pre- 
viously nonmuricidal rats given sufficient food and water so as not to 
lose weight and an intraperitoneal delta-9-THC dose of 10 or 20 
mg/kg/day developed mouse-killing behavior. 



References. — Preclinical Effects : Unlearned Behavior 

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2. Abel, E. L. Cannabis and aggression in animals. "Behavioral Biology," 14 :1- 
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3. Abel, E. L., Cooper. C. W. and Harris, L. S. Effects of delta-9-tetrahydro- 
cannabinol on body weight and brain electrolytes in the chicken. "Psycho- 
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4. Alves, C. X. and Carlini, E. A. Effects of chronic and acute administration 
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tetrahydrocannabinol on the development of rat offspring. '"Pharmacology Bio- 
chemistry and Behavior," 1 :203-206 (1973). 

8. Borgen, L. A., Lott. G. C. and Davis. W. M. Cannabis induced hypothermia : 
A dose effect comparison of crude marihuana extract and synthetic delta-9-tetra- 
hydrocannabinol in male and female rats. "Research Communications in Chemical 
Pathology and Pharmacology," 5 :621-627 (1973). 

9. Carder. B. and Olson, J. Marihuana and shock induced aggression in rats. 
"Physiology and Behavior," 8 :599-602 (1972). 

10. Carlini, E. A. and Gonzalez. S. C. Aggressive behavior induced by mari- 
huana compounds and amphetamine in rats previously made dependent on 
morphine. "Experentia," 28 :542-544 (1972). 

11. Carlini, E. A. and Lindsey, C. J. Pharmacological manipulations of brain 
catecholamines and the aggressive behavior induced by marihuana in REM- 
sleep-deprived rats. "Aggressive Behavior," 1:81-99 (1974). 

12. Carlini. E. A. and Masur, J. Development of aggressive behavior in rats by 
chronic administration of cannabis sat via (marihuana). "Life Sciences," 
8:607-620 (1969). 

13. Carlini, E. A. and Masur. J. Development of fighting behavior in starved 
rats by chronic administration of (1 )-delta-9-trans-tetrahydrocannabinol and 
cannabis extracts. "Communications in Behavioral Biology." 5:57-61 (1970). 

14. Chesher, G. B., Jackson, D. M. and Malor, R. M. Interaction of delta-9- 
tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice 
from electrically induced convulsions. "Journal of Pharmacy and Pharamaco- 
logy." 27:608-609 (1975). 

15. Chesher. G. B., Jackson. D. M. and Stormer. G. A. Interaction of cannabis 
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16. Consroe, P. F., Jones. B. C. and Akins, F. Delta-9-tetrahydrocannabinol- 
methamphetamine interaction in the rabbit. "Neuropharmacology," 14 :37-383 
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17. Consroe, P. F.. Jones, B. C. and Chin. L. Delta-9-tetrahydrocannabinol, 
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18. Cutler. M. G., Mackintosh, J. H. and Chance, M. R. A. Effects of cannabis 
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271-276 (1975). 

19. Drew, W. G. and Miller. L. L. Differential effects of delta-9-THC on loco- 
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(57) 

67-062—70 5 



58 

20. Drew, W. G., Miller, L. L. and Baugh, E. L. Effects of delta-9-THC, 
LSD-25 and scopolamine on continuous spontaneous alternation in the Y-maze, 
"Psychopharmacologia," 32:171-182 (1973). 

21. Dubinsky, B., Robichaud, R. C. and Goldberg, M. E. Effects of (-)-delta- 
9-trans-tetrahydrocannabinol and its selectivity in several models of aggressive 
behavior. "Pharmacology," 9 :204-21G (1973). 

22. Elsmore, T. F. and Fletcher, G. V. Delta-9-tetrahydrocannabinol : Aversive 
effects in rat at high doses. "Science," 175:911-912 (1972). 

23. Ely, D. L., Henry, J. P. and Jarosz, C. J. Effects of marihuana (delta- 
9-THC ) on behavior patterns and social roles in colonies of CBA rice. "Behavioral 
Biology," 13:263-276 (1975). 

24. Fernandes, M., Schabarek, A., Coper, H. and Hill, R. Modification of 
delta-9-THC-actions by cannabinol and cannabidiol in the rat. "P.sychopharma- 
cologia." 38 :329-338 (1974). 

25. Fernandes, M., Worning, X.. Christ, W. and Hill, R. Interactions of several 
cannabinoids with the hepatic drug metabolizing system. "Biochemical Pharma- 
cology." 22 :2981-2987 (1973). 

26. Fried, P. A. and Xieman, G. W. Inhalation of cannabis smoke in rats. 
"Pharmacology Biochemistry and Behavior," 1:371-378 (1973). 

27. Friedman, E. and Gershon, S. Effect of delta-9-THC on alcohol-induced 
sleeping time in the rat. "Psychopharmacologia," 39:193-198 (1974). 

28. Glick, S.D. and Milloy, S. Increased and decreased eating following THC 
administration. "Psychonomic Science," 29:6 (1972). 

29. Gluck, J.P. and Ferraro, D.P. Effects of delta-9-THC on food and water 
intake of deprivation experienced rats: "Behavioral Biology." 11 :39~-401 (1974). 

30. Gough, A. L. and OIley, J. E. Cannabis and amphetamine-induced sterotypy 
in rats. "Journal of Pharmacy and Pharmoeology," 27 :(!2-63 (1975). 

31. Hollister, L. E. Hunger and appetite after single doses of marihuana, al- 
cohol and dextroamphetamine. "Clinical Pharmacology and Therapeutics," 12: 
44-49 (1974)'. 

32. Huthsing, K., Fetterolf, D. and Ferraro, D. P. Modification of drinking 
behavior and water intake by delta-9-tetrahydrocannabinol in rats. Paper pre- 
sented to Rock Mountain Psychological Association, Salt Lake City, 1975. 

33. Jarbe, T. U. C. and Henriksson, B. G. Acute effects of two tetrahydrocanna- 
binols (delta-9-THC and delta-8-THC) on water intake in deprived rats: Impli- 
cations for behavioral studies of marihuana compounds. "Psychopharmacologia," 
30:315-322 (1973). 

34. Jones, B. C, Clark, D. L., Consroe, P. F. and Smith, H. J. Effects of (-)- 
delta-9-trans-tetrahydroeannabinols on social behavior of squirrel monkey dyads 
in a water competition situation. "Psychopharmacologia," 37:37-43 (1974). 

35. Jones, G. and Pertwee, R. G. A metabolic interaction in vivo between can- 
nabidiol and dolta-1-totrahydrocannabinol. "British Journal of Pharmacology," 
45:375-377 (1972). 

36. Karniol, I. G. and Carlini, E. A. The content of (-)-delta-9-trans-tetrahydro- 
cannabinol does not explain all biological activity of some Brazilian marihuana 
samples. "Journal of Pharmacy and Pharmacology," 24:833-835 (1972). 

37. Karniol, I. G. and Carlini, E. A. Pharmacologic interaction between canna- 
bidiol and dolta-9-tetrahydrocannabinol. "Psychopharmacologia," 33:53-70 
(1973). 

38. Kll'bey, M. M. The effect of delfa-94etrahydrooannabinol on innate and in- 
strumental fighting behavior in the mouse. Paper presented at the Southwestern 
Psychological Association. 1971. 

39. Kilbey, M. M.. Forbes, YV. B. and Olivetti. C. T)elta-9-tetrahydrfK\annabinol : 
Inhibition of deprivation and carbacol-lnduced water consumption in the rat 
after central and peripheral administration. "Behavioral Biology," 8:679-685 
(1973). 

40. Kilhey, M. M.. Moore, J. W. and Hall, M. Delta-9-tetrahydroeannabinol^ 
Induced inhibition of predatory aggression in the rat. "Psychopharmacologia, " 
:;i : 157-166 H973). 

41. Krantz, J. C, Berger, II. J. and Welch, B. L. Blockade of (-)-trans-delta- 
S-tetrahvdmcannabino! dep!ess;ml vflvri by cannabinol in mice. "American Jour- 
nal of Pharmacology," 143: 149-152 (1971). 

42. Knpfer, I)., Levin. E. and Bnrstein, S. IT. Studies on the effects of delta-1- 
tetrahydrocannafoinol (delta-1-THC) and DDT on the hepatic microsomal meta- 
bolism of delta-1-THC and other compounds in the rat. "Chemical Biological Inter- 
actions," 6:59-66 (1973). 



43. Malar, R., Jackson, D. M. and Chesher, G. B. The effect of delta-9-tetra- 
hydrocannabinol, cannabidiol and cannabinol on ether anaesthesia in mice. "Jour- 
nal of Pharmacy and Pharmacology," 27 : 610-612 (1975). 

44. "Marihuana and Health," Report to Congress from the Secretary, U.S. 
Department of Health, Education, and Welfare. Washington. D.C. : Government 
Printing Office, 1971. 

45. "Marihuana and Health," Second Annual Report to Congress from the 
Secretary of Health, Education, and Welfare. Washington, D.C. : Government 
Printing Office, 1972. 

46. "Marihuana and Health," Third Annual Report to Congress from the 
Secretary of Health, Education, and Welfare. Washington, D.C. : Government 
Printing Office, 1973. 

47. "Marihuana and Health," Fourth Annual Report to Congress from the Sec- 
retary of Health, Education, and Welfare. Washington, D.C. : Government Print- 
ing Office, 1974. 

48. McDonough, J. H., Manning, F. J. and Elsmore, T. F. Reduction of predatory 
aggres.-.ion of rats following administration of delta-9-tetrahydrocannabinol. "Life 
Sciences," 11 : 103-111 (1972). 

4!). Meehoulman, R. Marihuana chemistry. "Science," 168:1159-1160 (1970). 

50. Miczek, K. A. A behavioral analysis of aggressive behaviors induced and 
modulated by deita-9-tetrahydrocannabinol, pilocarpine, d-amphetamine and L- 
DOPA. "Activitas Nervosa Superior," in press. 

51. Miczek, K. A. Mouse-killing and motor activity : Effects of chronic delta-9- 
tetrahydrocannabinol and pilocarpine. "Psychopharmacologia," in press. 

5 1. Miczek. K. A. and Barry, H.. III. Delta-9-tetrahydrocannabinol and aggres- 
sive behavior in rats. "Behavioral Biology," 11 : 261-267 (1974). 

53. Miller, L. L. and Drew, W. G. Cannabis : Review of behavioral effects in 
animals. "Psychological Bulletin," 81 : 401-^17 (1974). 

54. Palermo Neto, J., Nunes, J. F. and Corvalho, F. V. The effects of chronic 
cannabis treatment upon brain 5-hydroxytryptamine, plasma cortieosterone and 
aggressive behavior in female rats with different hormonal status. "Psycho- 
1 1 rmacologia," 42 : 195-200 ( 1975) . 

55. Poddar, M. K. and Ghosh, J. J. Effect of cannabis extract, delta-9-tetra- 
hydrocannabinol and lysergic acid diethylamide on rat liver enzymes. "Biochemi- 
cal Pharmacology," 21 : 3301-3303 (1972). 

56. Pryor, G. T. and Braude, M. C. Interactions between delta-9-etrahydrocan- 
nabinol (THC) and phencyclidine (PC). "The Pharmacologists,'' 17: 182 (1975). 

57. Rosenkranz, H. and Braude, M. C. Rat inhalation of Turkish marihuana. 
"The Pharmacologist," 17 : 181 (1975). 

58. Santos, M., Sampaio, M. R. P., Fernandes, N. S. and Carlini. E. A. Effects of 
cannabis sativa (marihuana) on the fighting behavior of mice "Psychopharma- 
cologia," 8 : 437-444 (1966). 

59. Sjoden, P. O., Jarbe, T. U. C. and Henriksson, B. G. Influence of tetrahydro- 
cannabinols (delta-8-THC and delta-9-THC) on body weight, food, and water 
intake in rats. "Pharmacology Biochemistry and Behavior," 1:395-399 (1973). 

60. Sofia, R. D. and Barry, H. Acute and chronic effects of delta-9-tetrahydro- 
cannabinol on food intake by rats. "Psychopharmacologia," 39:213-222 ( 11)74 I . 

61. Takahashi, R. N. and Karnioi, I. G. Pharmacological interactions between 
cannabinol and delta-9-tetrahvdrocannabinol. "Psvchopharmacologia," 41:277- 
284 (1975). 

62. Ten Ham, M. and De Jong, Y. Absence of interaction between delta-9-tetra- 
hydrocannabinol (delta-9-THC) and cannabidiol (CBD) in aggression, muscle 
control and body temperature experiments in mice. "Psychopharmacologia," 41 : 
169-174 (1975). 

63. Ten Ham. M. and vanNoordwijk, J. Lack of tolerance to the effect of two 
tetrahydrocannabinols on aggressiveness. "Psychopharmacologia," 29 : 171-176 
(1973). 

64. Fyeno, E. T. Effects of delta-9-tetrahydrocannabinol on dominance behavior 
of the rat. "Federation Proceedings," 32 : 725 (1973) . 

65. Pyeno. E. T., Delta-9-tetrahydror-annabinol and the competitive behavior of 
the rat. "Federation Proceedings," 33 : 540 (1974). 

66. Uyeno, E. T. Delta-9-tetrahydrocannabinol administered to pregnant rats. 
"The Pharmacologist." 17: 181 (1975). 

67. Sassenrath, E. N. and Chapman, L. F. Tetrahydrocannabinol-induced mani- 
festations of the "marihuana syndrome" in group-living macaques. "Federation 
Proceedings," 34: 1666-1670 (1975). 



CHAPTER 5 

Preclinical Effects: Learned Behavior 

A review of the previous four Marihuana and Health reports (40, 
41, 42, 43) reveals that an extensive array of procedures and contexts 
have been used experimentally to study the effects of cannabinoids on 
the performance of learned behavior in animals. These preclinical 
behavioral experiments have provided a framework for, and guided 
the design of, subsequent human experimentation. Compared to pre- 
vious years, only a few experiments pertaining to cannabinoids and 
learned behavior have appeared this year. By and large these more 
recent experiments confirm previous findings; no particularly novel 
procedures have been employed nor have there been dramatically 
unpredictable results. In part, the decrease in activity in cannabinoid 
preclinical animal research on learned behavior is one sign of an 
increase in human cannabinoid-learning investigations. 

Several detailed taxonomies of learned behavior are possible. How- 
ever, for the purposes of the present report, learned behaviors will be 
categorized into those involving : avoidance learning and aversive con- 
trol ; reinforcement schedules and maze learning ; and discrimination 
learning. 

AVOIDANCE LEARNING AND ADVERSrVE CONTROL 

Whether or not cannabinoids enhance, depress or fail to affect the 
acquisition of avoidance behavior depends importantly on the canna- 
binoid time-course of action (45) and dose (22), as well as on the 
particular cannabinoid (28) and type of avoidance task used (52). 
However, when the behavior investigated is performance, rather than 
acquisition, of a learned avoidance task, cannabinoids have been reli- 
ably found to have disruptive effects (e.g., 9, 27, 28, 47) . 
t Additional reports of cannabinoid-induced impairment of estab- 
lished avoidance behavior have come from Tayal et. al. (53) and 
Pry or and Braude (51). In the latter study (51), it was further 
reported that delta-9-THC had a more than additive interaction with 
phencyclidine, over a wide range of doses for both drugs, in impairing 
conditioned avoidance behavior. The Tayal et. al. (53) experiment also 
found that tolerance develops to the disruption in avoidance perform- 
ance induced by an alcoholic extract of cannabis. This finding of tol- 
erance confirms and extends previous reports of cannabinoid tolerance 
development under learned avoidance tasks (e.g., 27, 39) . However, no 
new research has appeared to add to the finding (47) that delta-9- 
THC is cross tolerant with ethyl alcohol but not with morphine or 
chlorpromazine in a shuttle box avoidance task. 

With respect to aversive control situations other than avoidance 
learning, there have been several reports that cannabinoids reduce the 

(61) 



62 

conditioned emotional response of animals to a stimulus previously 
associated with an unavoidable electric shock, regardless of whether 
an appetitive or aversive situation is used to maintain baseline re- 
sponding (e.g., 23, -27). The usual interpretation given to this finding- 
is that cannabinoids act to reduce fear or anxiety. However, a fear- 
reduction interpretation does not always gain support from research 
with humans (50). 

Moreover, Ferraro and Bruce (16) have argued that previous con- 
ditional emotional response experiments have been, in part, con- 
founded by drug-state changes which occurred between the training 
and testing phases of these experiments. Indeed, when they compared 
the conditioned emotional responses of rats who had received all of 
their training and testing under 2.0 mg/kg delta-9-THC (intraperi- 
toneal injection) with nondrug control rats, delta-9-THC was found to 
increase the conditioned emotional response (14). 

Another factor which may be considered to temper the interpretation 
that cannabinoids reduce fear in aversive control situations is that 
delta-9-THC| has been found to have an analgesic effect in animals 
(35) and humans (48, 49). This was demonstrated by Dykstra and 
McMillan (12) who used a titration procedure to determine the in- 
tensity at which monkeys would maintain a continuously applied 
electric shock. It was found that an injection of 15.0 mg/kg delta-8- 
THC caused the monkeys to adjust the shock to a higher intensity than 
they had in the absence of the drug. 

In still another aversive control context, Corcoran et al. (8) have 
extended previous findings that delta-^-TIIC (14) and hashish extract 
(7) produce "bait shyness" in rats when paired with novel tastes. In 
the Corcoran et al. (H) study, deha-S-TIK\ CBD. and cannabiderol 
(CBG) all produced bait shyness. However, cannabichromene (CBC) 
did not produce a conditioned taste aversion in this aversive control 
situation. 

REINFORCEMENT SCHEDULES AND MAZE LEARNING 

Both operant and instrumental conditioning paradigms have been 
us^cl to study the effects of carmabiribicls on appetitively reinforced 
learned behavior in animals. In the operant conditio7iing context, 
Schedules of reinforcerrlent have received the most study. In the instru- 
mental conditioning context, m^^e or allev learning Has been the usual 
baseline for determining calmabShoid effects. 

Following the outline established in the fourth Marihuana and 
Health report (43), experiments dealing with cannabinoid-reinforce.- 
ment schedule interactions will be categorized in two major types: 
Type I experiments which focus on. changes in schedule controlled 
responses, and Type IT experiments in which such responses merely 
provide a baseline for the study of drug-related parameters. 

The bulk of the earlier cannabinbid research with reinforcement 
schedules was of the first type (cf., 40, II, 42, 43). What little research 
of this type there has been in the past two years (e.g., 9, 20, 55) 1ms 
mainly tended to replicate and confirm the findings from the earlier 
Research even frhere more complicated reinforcement schedules have 
been used (2). Taken all together, the research demonstrates that 



63 

behavior under reinforcement schedule control is reactive to delta-9- 
THC and delta-8-THC as well as to ether constituents of cannabis 
(10, 21). In general, such behavior is depressed in a dose-related 
manner by cannabinoids, although under schedules which tend to 
generate low response rates, a bi-phasic dose-response function or an 
alternation between periods of no responding and increased rates of 
responding are sometimes observed. 

Although only limited attention has been given to the effects of 
cannabinoids on the acquisition and extinction of operant behaviors 
(18), the now very extensive literature on the relationship between 
cannabinoids and performance of schedule controlled responses has 
stimulated the use of such responses as baselines in Type II studies of 
drug-related parameters. 

Among other things, reinforcement schedule baselines have been 
used in the past two years to study : Between-cannabinoid comparisons 
(36) ; cross-tolerance between cannabinoids and other drugs (47) ; and 
differences between drug vehicles and routes of cannabinoid adminis- 
tration (1, 15, 17). An operant paradigm has also been used to investi- 
gate the interaction between deIta-9-THC and cannabidiol. Davis and 
Borgen (10) found that intraperitoneal injections of 3.0 mg/kg delta- 
9-THC suppressed schedule controlled responding in rats while 25.0 
mg/kg CBD did not. Similarly, intramuscular injection of 1.0 mg/kg 
delta-9-THC suppressed responding in pigeons while 50.0 mg/kg CBD 
did not. However, when animals were pretreated with their respective 
CBD doses, the THC induced suppression of responding was reduced. 

An instance of the Type II reinforcement schedule experiment was 
recently performed by Dykstra et al. (13) These researchers injected 
pigeons responding under variable interval, fixed ratio, and fixed in- 
terval schedules with a range of delta-9-THC and SP-111 doses (.3 to 
18.0 mg/kg intramuscular injection administered either one or two 
hours before the start of the experimental session). SP-111 as a water 
soluble ester of deltn-9-THC which bears a basic amino function (56). 
Both drugs produced a dose-related suppression of reinforcement 
schedule responding although delta-9-THC was three to six times more 
potent than SP-1 11 and had a faster time of onset. 

A large number of both types of reinforcement schedule experi- 
ments have investigated the development of tolerance under the can- 
nabinoids (e.g., 1, 2. 20, 36, 38, 47). These experiments have uniformly 
shown that tolerance readily develops in animals to cannabinoid- 
indueed suppressant effects on operant responding. However, two 
studies have shown that, in this situation, tolerance development to 
delta-9-THC is due to the animals responding under the influence of 
the drug rather than to the mere exposure of the animals to delta-9- 
THC (5, 38). Moreover, Frankenheim (20) observed that repeated i.p. 
injections of delta-8-THC (10.0 and 17.8 mk/kg) tended to increase 
the sensitivity of rats to a response rate-increasing effect of the drug 
under a differential reinforcement of low rate schedule of reinforce- 
ment. This increased sensitivity was likened by Frankenheim (20) to 
the reverse tolerance sometimes reported for marihuana effects in 
humans. 

Compared to operant reinforcement schedule research, the effects of 
cannabinoids on the acquisition and performance of instrumental maze 



64 

or alley-way responding have not received extensive study. A Cana- 
dian study, not yet published, has found that permanent impairment 
of maze learning ability in rats occurred following six months of treat- 
ment with oral doses of either ethanol or cannabis extract. While the 
doses of THC and alcohol were both relatively high (20 mg THC/kg) 
the authors point out the animals were visibly intoxicated for "only 
about four hours after each dose, gained weight normally and were 
in good general health throughout the experiment." Based on the de- 
gree of intoxication, they argue that the research may be relevant to 
possible learning impairment under conditions of unusually heavy 
human use (57). Based on previously published literature, it may be 
concluded that the cannabinoids impair reinforced and latent learning 
in a variety of instrumental conditioning situations including the Y 
maze, T maze, Lashley III maze and straight alley (11, 29, 44, 46, 54) . 

DISCRIMINATION LEARNING 

The effects of cannabinoids on discrimination learning were re- 
viewed for the first time in the previous Marihuana and Health report 
(43) under two subtopics: 1) the effects of cannabinoids on the per- 
formance of discriminations based on exteroceptive stimuli, and 2) 
the acquisition of stimulus control of behavior based on the presence 
or absence of cannabinoids. 

As there have been few experiments published since the last report 
which describe the effects of cannabinoids on discrimination learning 
with exteroceptive stimuli, only a brief summarization of the existing 
literature will be made herein. 

In general, the effects of cannabinoids on established stimulus dis- 
criminations are influenced by the same variables as determine the 
effects of other psychotropic drugs on discrimination performance 
(cf., 43). More specifically, disruption of discrimination performance 
by cannabinoids is more likely if the discrimination is complex rather 
than simple and if the discrimination is successive rather than simul- 
taneous. The typical cannabinoid-induced disruption of discrimination 
performance is the result of dose-related decreases in responses to the 
stimulus associated with reinforcement and corresponding increases in 
responses to the stimulus associated with nonreinforcement. Finally, 
and in accord with the effects of most other psychotropic drugs, during 
generalization testing delta-9-TIIC reduces total response output but 
does not typically alter the slope of the generalization gradient. 

It is now well established that animals can learn to discriminate 
between the presence of cannabinoids and a vehicle-control solution 
(3, 4, 19, 25, 31, 32, 33, 37). Jarbe et. al. (33) used an experimental 
procedure which is prototypic of research on this topic. Gerbils trained 
in a T maze were required to make discriminative choices based on 
whether delta-9-TPIC or drug vehicle alone had been injected prior to 
the training session. As is the usual outcome in cannabinoid stimulus 
studies of this sort, Jarbe et. al. (33) found that the delta-9-THC 
discrimination was acquired in a dose-related manner (from 0.5 to 16.0 
mg/kg, i.p.), Furthermore, decreasing the dose or increasing the 
injection-test interval from that used in training led to a decrease in 
delta-9-THC associated choices. One final aspect of this study which 



65 

is unique is that pentobarbital (20.0 mg/kg) interacted in a more than 
additive fashion with delta-9-THC to determine drug versus control 
solution choice responses. 

The delta-9-THC discrimination paradigm has also been used 
recently to compare the potency of different routes of drug administra- 
tion (3, 32). As compared to intraperitoneal administration, delta-9- 
THC administered orally or by inhalation had stronger stimulus prop- 
erties while lesser stimulus properties were manifest after intravenous 
administration of delta-9-THC. 

Although some quantitative differences exist, it now appears that 
the stimulus properties of delta-9-THC are interchangeable with delta - 
8-THC, ll-OH-delta-8-THC. cannabis extract, and hashish smoke (3. 
32). However, neither CBD or CBX seemingly produce THC-like 
stimulus properties (32). Furthermore, a wide range of drugs from 
several pharmacological classes have been shown not to be interchange- 
able, in terms of stimulus properties, with delta-9-THC. Thus, there is 
support for a hypothesis that the active cannabinoids may have a 
unique mode of pharmacological action. 

One final aspect of the cannabinoid-stimulus discrimination para- 
digm merits further study. Of concern is whether or not tolerance 
develops to the drug-stimulus properties of delta-9-THC. There have 
been three studies which address this concern. One study supports the 
development of tolerance (26) . one provides indirect evidence support- 
ing tolerance development (30), and finally, one provides data in- 
directly supporting a lack of tolerance development (6). Until addi- 
tional experiments are performed it seems appropriate to conclude 
tentatively that a slow, and perhaps partial, tolerance develops to the 
stimulus properties of delta-9-THC. 

State-dependent learning refers to the phenomenon that animals per- 
form better if trained and tested under the influence of a drug than if 
a drug-state change occurs between the training and testing phases of 
an experiment. State-dependent learning has been shown for delta-8- 
THC and delta-9-THC (cf., 45). However, it is not clear from the 
THC literature whether or not symmetric disruptive effects are ob- 
tained between a change from a drugged to a nondrugged state (D- 
XD) and a change from a nondrugged to a drugged state (XD-D). 
Both symmetric and asj-mmetric state-dependent effects have been re- 
ported for THC (24) . In the case of asymmetric effects, a change from 
the XD to D state (22) . Johansson et al. (34) have shown that delta-8- 
THC will reliably induce asymmetric state dependency of this latter 
type if animals are first made tolerant to the acute disruptive effects 
of the drug. 



References. — Preclinical Effects : Learned Behavior 

1. Abel, E. L., McMillan, D. E. and Harris, L. S. Delta-9-tetrahydroeannabinol : 
Effects of route of administration on onset and duration of activity and tolerance 
development. "Psychopharmacologia," 35: 29-38 (1974). 

2. Adams, P. M. and Barratt, E. S. Effects of acute and chronic marijuana on 
the i>erformance of a complex reinforcement schedule in the squirrel monkev. 
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3. Barry, H. and Krimmer, E. C. Discriminative delta-9-tetrahydrocannabinol 
stimulus tested with several doses, routes, intervals and related compounds. 
Paper presented at the International Conference on the Pharmacology of Can- 
nabis, Savannah, 1974. 

4. Barry, H. and Kubena, R. K. Discriminative stimulus characteristics of 
alcohol, marihuana, and atropine. "Drug Addiction,"' Vol. 1. Edited by Singh, 
J. M., Miller. L. and Lai, H. New York : Futura, 1972. 

5. Bruce, P. D. and Ferraro, D. P. Learned tolerance to delta-9-tetrahydrocan- 
nabinol in pigeons. Paper presented to Rocky Mountain Psychological Association, 
Salt Lake. 1975. 

6. Bueno, O. F. A. and Carlini. E. A. Dissociation of learning in marihuana 
tolerant rats. "Psyehopharmaeologia," 25 : 49-56 (1972). 

7. Corcoran. M. E. Role of drug novelty and metabolism in the aversive effects 
of hashish injections in rats. "Life Sciences," 12 : 63-72 (1973). 

8. Corcoran, M. E., Bolotow, I., Amit, Z. and McCaughran, J. Conditioned taste 
aversions produced by active and inactive cannabinoids. "Pharmacology Bio- 
cbemistry and Behavior." 6 : 725-728 (1974). 

9. Davis. T. R. A., Kensler, C. J. and Dews, P. B. Comparison of behavioral 
effects of nicotine, d-amphetamine, caffeine and dimethyleptyl tetrahydrocan- 
nabinol in squirrel monkeys. "Psychopharmacologia," 32: 51-65 (1973). 

10. Davis, W. M. and Borgen, L. A. Effects of cannabidiol and delfa-9- 
tetrahydrocannabinol on operant behavior. "Research Communications in Chemi- 
cal Pathology and Pharmacology," 9 : 453-462 (197-1 ) . 

11. Drew, \V. C, Miller, L. L. and Baugh, E. L. Effects of delta-9-THC. LSD-25 
and scopolamine on continuous spontaneous alternation in the Y-maze. "Psycho- 
pharmacologia," 32: 171-182 (1973). 

12. Dyksfra, L. and McMillan. D. E. Shock-intensify adjustment by squirrel 
monkeys under a titration procedure following administration of morphine, nalor- 
phine, pentazocine, propoxyphene, delia-S-tet rahydrocannabinol (del(a-8-TIIC) 
or chlorpromazine. "Federation Proceedings," 33: 516 (1974). 

13. Dykstra. L. A., McMillan. D. E. and Harris. L. S. Effects of delta-9-THC 
and a water soluble ester of delfa-9-THC on scheduh'-eontrolled behavior. 
"Pharmacology Biochemistry and Behavior." 3 : 29-32 ( 1975). 

14. Elsmore. T. F. and Fletcher. C. V. Delta-!)-tot rahydrocannabinol : Aversive 
effect^ in rai at high doses. "Science." 175: 911-912 ( 1972). 

15. Elsmore. T. F. and Manning, F. J. Time course and dose-response effects of 
orally administered deita-9-THC on interval schedule performance of the pat. 
"Life Sciences." 15 : 4S1-4K9 ( 197! | . 

16. Ferraro, I). P. and Bruce, P. D. Marihuana-induced enhancement of a con- 
ditioned emotional response. Paper presented at the Rocky Mountain Psycho- 
logical Association, Salt Lake. 1975. 

17. Ferraro, I). P. and Cluck. J. P. Effects of oral delta-9-tot rahydrocannabinol 
on operant reinforcement schedule performance in rats. "Pharmacology," 
11 : 65 69 (1974). 

is. Ferraro, I). P.. Cluck, .7. P. and Herndon, C. P.. Acquisition and extinction 
of variable interval schedule behavior by rats under dolta-9-tefrahydrocannabinol. 
"Pharmacology Biochemistry and Behavior," 2 : 487-491 (1974). 

(66) 



67 

19. Ferraro, D. P., Gluck, J. P. and Morrow, C. W. Temporally related stimulus 
properties of delta-9-tetrahydrocannabinol in monkeys. "Psychopharmacologia," 
35:305-316 (1974). 

20. Frankenlieim, J. M. Effects of repeated doses of L-delta-8 ? £rans-tetrahydro- 
cannabinol on schedule-controlled temporally-spaced responding of rats. "Psycho- 
pharmacologia," 38:125-144 (1974). 

21. Frankenlieim, J. M., McMillan, D. E. and Harris, L. S. Effects of delta-9- 
and delta-8-tetrahydrocannabinol and eannabinol on schedule-controlled behavior 
of pigeons and rats. "Journal of Pharmacology and Experimental Therapeutics," 
178:241-253 (1971). 

22. Goldberg, M. E., Hefner, M. A., Robichaud, R. C. and Dubinsky, B. Effects 
of delta-9-tetrahydrocannabinol (THC) and chlordiazepoxide (CDP) on state- 
dependent learning : Evidence for asymmetrical dissociation. "Psychopharma- 
cologia," 30: 173-184 (1973). 

23. Gonzalez, S. C, Karniol, I. G. and Carlini, E. A. Effect of cannabis satira 
extract on conditioned fear. "Behavioral Biology," 7 : 83-94 (1972). 

24. Henriksson, B. G. and Jarbe, T. The effect of two tetrahydrocannabinols 
(delta-9-THC and delta-8-THC) on conditioned avoidance learning in rats and 
its transfer to normal state conditions. "Psychopharmacologia," 22 : 23-30 (1971). 

25. Henriksson, B. G. and Jarbe, T. Delta-9-tetrahydrocannabinol used as a 
discriminative stimulus for rats in position learning in a T-shaped water maze. 
"Psychonomic Science," 27 : 25-26 (1972). 

26. Hirsehorn, 1. I), and Rosencrans, J. A. Morphine and delta-9-tetrahydro- 
cannabinol : Tolerance to the stimulus effects. "Psychopharmacologia," 36 : 243- 
253 (1974). 

27. Houser, V. P. The effects of delta-9-tetrahydrocannabinol upon fear-moti- 
vated behavior in squirrel monkeys. •"Physiological Psychology," 3:157-161 
(1975). 

28. Izquierdo, I. and Nasselo, A. G. Effects of cannabidiol and of diphenyl- 
hydantoin on the hippocampus and learning. "Psychopharmacologia," 31 : 321- 
332 (1973). 

29. Jarbe, T. V. C. and Henriksson, B. G. Effects of delta-8-THC and delta-9- 
THC on the acquisition of a discriminated positional habit in rats. "Psycho- 
pharmacologia," 31 : 321-332 (1973). 

30. Jarbe, T. U. C. and Henriksson, B. G. Open-field behavior and acquisition 
of discriminative response control in delta-9-THC tolerant rats. "Experientia," 
29:1251-1253 (1973). 

31. Jarbe, T. U. C. and Henriksson, B. G. State dependent learning with tetra- 
hydrocannabinols and other drugs. "Ciencia E Cultura," 25: 752 (1973). 

32. Jarbe, T. U. C. and Henriksson, B. G. Discriminative response control pro- 
duced with hashish, tetrahydrocannabinols (delta-8-THC and delta-9-THC), and 
other drugs. "Psychopharmacologia," 40: 1-16 (1974). 

33. Jarbe, T. U. C, Johansson, J. O. and Henriksson, B. G. Delta-9-tetrahydro- 
cannabinol and pentobarbital as discriminative cues in the Mongolian gerb.il 

(Meriones unguiculatus). "Pharmacology Biochemistry and Behavior," 3:403- 
410 (1975). 

34. Johansson, J. O., Henriksson, B. G. and Jarbe, T. U. C. Effects of delta-S- 
THC on dissociation of conditioned avoidance responding in tolerant and non- 
tolerant rats "Physiological Psychology," 2 : 431-432 (1974). 

35. Kaymakcalan, S., Turker, R. K. and Turker, M. N. Analgesic effect of delta- 
8-tetrahydrocannabinol in the dog. "Psychopharmacologia," 35:123-128 (1974). 

36. Kosersky, D. S., McMillan, D. E. and Harris, L. S. Delta-9-tetrahydrocan- 
nabinol and ll-hydroxy-9-delta-9-tetrahydrocannabinol : Behavioral effects and 
tolerance development. "Journal of Pharmacology and Experimental Therapeu- 
tics," 189:61-65 (1974). 

37. Kubena, R. K. and Barry, H. Stimulus characteristics of marijuana com- 
ponents. "Nature," 235: 397-39S (1972). 

38. Manning, F. J. Acute tolerance to the effects of delta-9-tetrahydrocanna- 
binol on spaced responding in rhesus monkeys. "Pharmacology Biochemistry and 
Behavior," 2:603-607 (1974). 

39. Manning, F. J. Tolerance to effects of delta-9-tetrahydrocannabinol (THC) 
on free-operant shock avoidance. "Federation Proceedings," 33:481 (1974) . 

40. "Marihuana and Health," Report to Congress from the Secretary, U.S. 
Department of Health, Education, and Welfare. Washington, D.C. : Government 
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68 

41. "Marihuana and Health," Second Annual Report to Congress from the Sec- 
retary of Health, Education, and Welfare. Washington, D.C. : Government Print- 
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42. "Marihuana and Health," Third Annual Report to Congress from the Sec- 
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44. Miller, L. L. and Drew, W. G. Impairment of latent learning in the rat by a 
marihuana component. "Nature," 8: 421-426 (1973). 

45. Miller, L. L. and Drew, W. G. Cannabis : Review of behavioral effects in 
animals. "Psychological Bulletin," 81 : 401-417 (1974). 

46. Miller, L. L., Drew, W. G. and Wilder, A. Comparison of delta-9-THC, 
LSD-25 and scopolamine on non-spatial single alternation performance in the 
runway, "Psycliopharmacologia," 28: 11 (1973). 

47. Newman, L. M., Lutz, M. P. and Domino, E. F. Delta-9-tetrahydrocanna- 
binol and some CNS depressants: Evidence for cross tolerance in the rat. 
"Archives Internationales de Pharmacodynamic," 207:254-259 (1974). 

48. Noyes, R., Brunk, S. F., Avery, D. H. and Canter, A. The analgesic prop- 
erties of delta-9-tetrahydrocannabinol and codeine. "Clinical Pharmacology and 
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49. Noyes, R., Brunk, S. F., Baram, D. S. and Canter, A. Analgesic effect of 
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experimentally induced anxiety? "Psychopharmacologia," 40: 205-210 (1974). 

51. Pryor, G. T. and Braude, M. C. Interactions between delta-9-tetrahydro- 
cannabinol (THC) and phencyclidine (PC). "The Pharmacologist," 17:182 
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52. Robichaud, R. C, Hefner, M. A., Anderson, J. E. and Goldberg, M. E. Effects 
of delta-9-tetrahydrocannabinol (THC) on several rodent learning paradigms. 
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53. Tayal, G., Gupta, L., Agarwal, S. S. and Arora, R. B. Effects of cannabis 
on conditioned avoidance response and brain monoamine oxidase activity in rats. 
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ings of the American Psychological Association," 997-998 (1973). 

55. Wagner, M. J., Greenberg, I., Fraley, S. and Fisher, S. Effects of delta-9- 
tetrahydrocannabinol and ethyl alcohol on adjunctive behavior and the lateral 
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56. Zitco, B. A., Howes, J. F., Razdan, R. K., Dalzell, H. C, Sheehan, J. C. and 
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177:442 (1972). 

57. Fehr, K. A., Kalant, H., Le Blanc, A. E. and Knox, G. V. Permanent learn- 
ing impairment after chronic heavy exposure to cannabis or ethanol in the rat. 
Personal communication. 



CHAPTER 6 

Preclinical Chronic Effects : Unlearned and Learned Behavior 

There is no unequivocal answer to the question of whether or not 
tolerance develops to cannabinoid-induced effects on unlearned and 
learned behavior. In certain response systems, tolerance clearly de- 
velops and is characterized by its rapid development and large magni- 
tude. Indeed, in the past two years tolerance has been demonstrated for 
both unlearned and learned responses in a range of animal species 
under a variety of drug conditions in studies examining: unlearned 
motor responses in rats (4) ; spontaneous activity in mice (3) ; condi- 
tioned avoidance performance in rodents and monkeys (30, 39, 46) ; 
analgesia in dogs (31) ; and reinforcement schedule performance in 
pigeons, monkeys and rats (2, 5, 21, 32) . 

In addition to demonstrations that tolerance to the cannabinoids can 
develop in unlearned and learned behavioral situations, there have been 
several experiments which serve to elucidate some of the determinants, 
both pharmacological and extrapharmacological, of tolerance develop- 
ment to the cannabinoids. These latter experiments encompass a wide 
variety of situations and parameters and, in some instances, suggest 
constraints on the generalit} 7 or pervasiveness of tolerance to the can- 
nabinoids. The studies described below are representative of these 
experiments. 

Abel et al. (1) have shown that tolerance to the effects of delta-9- 
THC on reinforcement schedule responding develops in pigeons at 
about the same rate after intramuscular, intravenous, or peroral ad- 
ministration. Tolerance also follows a similar course for delta-9-THC 
and its metabolite ll-OH-delta-9-THC (32). However, Fernandes et 
al. (13) have suggested that CBD interacts with THC to enhance the 
tolerance development to THC. 

Barns and Fried (4) have shown that the age of the subject at the 
time of first exposure to delta-9-THC interacts with later tolerance 
development. Rats first received delta-9-THC when immature de- 
veloped tolerance more rapidly as adults than did rats who were adults 
when first drugged. 

Rate of tolerance appears to depend as well on : the amount of prior 
training on a learning task (40) ; and the type (39), parameter values 
(19, 24, 30), and complexity of the learned task (16, 43). In general, 
as the amount of prior training is decreased and the difficulty of the 
learned task is increased, tolerance develops more slowly or does not 
develop at all. Another behavioral variable that seems to determine 
the rate of tolerance development is the behavioral consequences pro- 
duced by delta-9-THC (14, 36). For example, in one experiment (36) 
tolerance developed to delta-9-THC much more rapidly if delta -9- 
THC acted to increase the number of shocks received by rats working 

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70 

under a conditioned avoidance task. In this same learning context, 
it appears that the development of delta-9-THC tolerance in appetitive 
reinforcement situations is facilitated if animals are given the oppor- 
tunity to respond under the influence of the drug rather than being 
given mere exposure to the drug. This latter finding has been reported 
for rats (7), pigeons (5), monkeys (35), and chimpanzees (18). 

On the basis of findings such as the above, Fcrraro (15) has 
followed the lead of others (12, 25) in proposing a behavioral model 
■of marihuana tolerance. The essence of this position is that learning 
or drug-behavior interactions account, in part, for some of the char- 
acteristics of tolerance development to delta-9-THC. The pharma- 
cological mechanism underlying tolerance development to the canna- 
binoids is not definitely known (cf., 37). However, there is evidence 
which suggests that the development of tolerance to delta-9-THC may 
proceed by more than one pharmacodynamic mechanism of action. 
For example, Anderson et. al. (3) found that both the time of onset 
and the duration of tolerance to delta-9-THO differed in mice with 
respect to drug effects on intestinal motility, temperature, and loco- 
motor activity. As these researchers concluded, it seems unlikely that 
any one mechanism, such as metabolic tolerance, could account for the 
obtained differences in tolerance development over so wide a range 
of response systems. Other experimenters have provided data which 
suggest that delta-9-THO tolerance is not solely metabolic or drug dis- 
tributional (10. 38). Obviously, additional research will be necessary 
in order to specify just what pharmacodynamic and learning factors 
arc important in determining the development of tolerance to 
marihuana. 

Admittedly, it is not possible to make direct comparisons between 
different cannabinoid tolerance experiments since they often differ in 
nonsvstematic ways with respect to such variables as number, level and 
distribution of drug doses, behavioral task and species of subject. 
Nevertheless, it must be noted that the literature contains a fair 
number of experiments where a lack of tolerance development to the 
cannabinoids has been reported. This rosnlt has been found for rodents 
in such situations as: open-field behavior (42); isolation-induced 
aggression (11) ; food and water intake (23, 44) : and discrimination 
learning based on exteroceptive (20) or drug-prodnced stimuli (6). 
By contrast. Frankenheim (22) has recently reported that repeated 
injections of delta-8-THC produce an increased sensitivity to some of 
the effects produced by this drug on reinforcement schedule-controlled 
responding in rats. This increased sensitivity was likened by Franken- 
heim (22) to a reverse tolerance effect. 

With respect to other chronic effects of the cannabinoids, two experi- 
ments have failed to find any residual effects on learned behavior fol- 
lowing discontinuance of delta-9-THC previously administered for 
L50 consectil ive days (18) or a periodically for seven months (17). And, 
with the exception of one experiment (41), animals have not been 
observed to self-administer cannabinoids. More specifically, monkeys 
do not self-administer delta-9-THC after receiving the drug for a 
month or when offered it as a substitute for cocaine (26). Rats forced 
to drink cannabis extract or hashish suspensions for long periods of 
time (up to 120 days) reject the drug in favor of a control solution 



71 

(9, 33). Finally, mice are reluctant to consume food pellets containing 
delta-9-THC even after subsisting on the pellets for over two months 

( 34 >-. 

It is noteworthy that no behavioral symptoms of abstinence or with- 
drawal were reported in the above experiments at the termination of 
the forced drug regimens used (cf., 26, 33). One further experiment 
by Chesher and Jackson (8) reported the absence of an abstinence syn- 
drome after withdrawal of cannabis extract administered in oral doses 
equivalent to up to 80.4 mg/kg delta-9-THC for 11, 13, and 28 days. 
In this study, mice were tested for their convulsive thresholds to pen- 
tylenetetrazol between six hours and six days following termination of 
the cannabis drug regimen. No differences were obtained between drug 
and control animals. 

Despite the above evidence to the contrary, there were two reports 
last year that were suggestive with respect to delta-9-THC-procluced 
dependence and abstinence symptoms (29, 45). In the better controlled 
of these experiments (45), rats were administered naloxone hydro- 
chloride after a five-week pretreatment period with delta-9-THC (8.0 
to 32.0 mg/kg, intraperitoneal injection). The rats exhibited narcotic- 
like withdrawal symptoms including diarrhea, teeth chattering and 
"wet dog" shakes. Two additional experiments published this year 
(27, 28) demonstrated that delta-8-THC and delta-9-THC, but not 
CBD, reduce the abstinence symptoms precipitated by naloxone hydro- 
chloride in morphine-dependent rats. In the first of these (27), delta- 
9-THC doses of 5.0 and 10.0 mg/kg administered by the intraperi- 
toneal route one hour before naloxone administration significantly 
reduced the frequency of wet shakes and diarrhea in the morphine 
treated rats. On the basis of their data, Hine et al. (27, 28) concluded 
that the tetrahydrocannabinols may have some therapeutic utility in 
clinical narcotic detoxification programs. 



References. — Preclinical Chronic Effects : Unlearned and Learned 

Behavior 

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2. Adams. P. M. and Barrett, E. S. Effects of acute and chronic marijuana 
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20. Fetterolf, D. J. and Ferraro, D. P. Retardation of the acquisition of a 
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tetrahydrocannabinol on schedule-controlled temporally-spaced responding of 
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22. Frankenheim, J. M., McMillan, D. E. and Harris, L. S. Effects of delta-9- 
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30. Houser, V. P. The effects of delta-9-tetrahydrocannabinol upon fear-moti- 
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31. Kaymakcalan, S., Turker, R. K. and Turker, M. N. Analgesic effect of delta- 
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32. Kosersky, D. S.. McMillan, D. E. and Harris, L. S. Delta-9-tetrahydrocan- 
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36. Manning. F. J. Tolerance to effects of delta-9-tetrahydrocannabinol (THC) 
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39. Newman, L. M., Lutz, M. P. and Domino, E. F. Delta-9-tetrahydrocanna- 
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marihuana extract : E1EG and behavioral effects of chronic oral administration 
in rhesus monkeys. ••Psychopharmacologia," 37: 225-233 (1974). 

40. Tayal, G., Cupta, L., Agarwal, S. S. and Arora, R. B. Effects of cannabis 
on conditioned avoidance response and brain monoamine oxidase activity in rats. 
"Indian Journal of Experimental Biology," 12 : 375-376 (1974). 



CHAPTER 7 

Human Effects 

acute effects 

A person ingesting or smoking cannabis experiences a fairly pre- 
dictable sequence of physiologic and psychologic changes which last 
a few hours and then gradually disappear. Although dose admin- 
istered and individual differences in personality, expectations, setting 
and past drug experience all contribute to varied consequences from a 
given dose of cannabis, the variability in acute effects from cannabis 
seems no greater than with any other psychoactive drug. A number of 
reviews and collections of papers have appeared during the past year 
which attempt to cover the vast amount of information accumulating 
about the acute and chronic effects of cannabis (7, 27. 43. 70, 82. 114). 
Some authors have attempted to consider the research findings in the 
context of political-social decisions (43, 1?)?)) and point out the lacunae 
in the data as well as the well established facts (43). The continuing 
research efforts this past year have attempted to fill some of the gaps. 
Emphasis has been placed on the chemistry of cannabis constituents, 
less obvious effects such as hormonal changes and the initial studies of 
acute drug effects in populations other than those made up of self- 
selected marihuana users. 

Activity of natural and synthetic cannabinoids 

Detailed pharmacokinetic studies of delta-8-THC in man using mass 
fragmentographic techniques indicate a similar time course and clear- 
ance pattern to that seen with delta-9-THC (103). A very rapid alpha 
phase was followed by a slower phase. While blood levels did not al- 
ways predict physiological and psychological effects, they paralleled 
heart rate changes well. 

DMHP. a synthetic cannabinoid. differs from delta-9-THC by hav- 
ing a double bond in the 6a. 10a positions. Intravenous administration 
in man produced profound cardiovascular effects but only minimal 
psychological effects (102). As is the case with natural cannabinoids, 
hydroxylation seemed to be the major metabolic pathway. 

Metabolism of cannabinoids and biocliemixtry 

Metabolites. — Although studies of a major metabolite of clelta-9- 
THC. 11-hydroxy-THC. indicate it is pharmacologically active, some 
question remains whether it is the onlv metabolite or whether delta- 
9-THC needs to be hydroxylated to 11-hydroxy-THC before the THC 
is active (72). In an attempt to clarify these issues. Hollister sorted 
people into fast and slow hydroxylators on the basis of antipyrine 

(75) 



76 

and phenylbutazone plasma disappearance rates. THC and these drugs 
are metabolized by the same liver microsomal enzyme system (169). 
There was no difference in speed of onset, intensity or duration of 
effects after intravenous injection of delta-9-THC when the two groups 
were compared (72). Such results suggest 11-hydroxy-THC may not 
be the sole source of delta-9-THC effects. Another group of investi- 
gators found 11-hydroxy-THC to leave the plasma more rapidly than 
THC, suggesting THC may, in fact, be more potent (133). 

A number of additional marihuana metabolites have been reported 
in a series of studies (83, 84, 85) and for the first time, unchanged 
delta-9-THC was identified in the urine using conventional thin layer 
chromatographic techniques in amounts estimated at .01-.005% of 
the dose (74). Xew extraction procedures revealed a previously 
ignored fraction containing abundant metabolites (83) including 
many polar metabolites (84). The exact identity and activity has yet 
to be determined. In a review of structure activity relationships of 
cannabinoids in man, Hollister concluded that the potency of the THC 
molecule is altered by changing length of side chains, or by metabolic 
hydroxylations. Xo material has yet been formed in nature in cannabis 
itself or in THC metabolites which differ qualitatively from THC 
(71). There is now evidence indicating the human small intestinal 
mucosa, as well as the liver, can hydroxylate THC (59). 

Cannabinoid interactions. — Studies of the possible interaction be- 
tween delta-9-THC and the other two major cannabinoids of mari- 
huana — cannabinol (CBX) and cannabidiol (CBD) — are not com- 
pletely consistent in their conclusions. Hollister found only slight 
interaction between THC and CBD. After CBD. there was a delayed 
onset and prolonged effects of THC that were slightly more intense 
(73) . The magnitude of the interactions was so small as to be clinically 
insignificant. However, other experiments in man with different 
samples of marihuana plant material containing varied amounts of 
CBN and CBD found differences in effects, possibiv due to differing 
proportions of CBX. CBD and THC (IS). A subsequent study by the 
same group found large doses of CBD to block many of the effects 
of THC (8G). A possible complicating factor in cannabinoid inter- 
action studies is the issue of instability of various synthetic and natu- 
rally occurring cannabinoids (165). 

I ii-ieri'ciionx with other drugsi — Besides CBD and CBX, other drug 
interactions with THC have been investigated in man. Secobarbital 
and smoked marihuana had additive effects on subjective responses 
and psychomotor impairment (32). Subjects had difficulty distin- 
guishing 150 mg of secobarbital from W J5 micrograms of THC kg. 
When amphetamine and smoked marihuana were combined, additive 
effects of heart rate and blood pressure and subjective symptoms were 
observed, but no interaction effect on psychomotor performance was 
found (17). Based on the assumption that TTTC interferes with 
cholinergic brain mechanisms, physostigmine decreased the tachy- 
cardia, and conjunctival injection, but had little effect on psychological 
changes (54). Little potentiation of narcotic drug effects was noted 
in a stuoty evaluating THC as a prc-nnesthet ic a&enl! (77). Animal 
studies indicate thai whatever the drug combination the depressant 
effects of THC tend to predominate (138). 



77 

Assay techniques. — A great deal of effort has gone into the develop- 
ment of practical assays of cannabinoid levels in man. Such measures 
are needed not only for research purposes, but would be useful clin- 
ically and in law enforcement (particularly in cases where intoxication 
while driving an automobile is an issue). A number of techniques 
using saliva and TLC with mass spectrometry (81), radioimmuno- 
assay of blood and urine (105, 160) , and gas chromatography of blood 
(106) have been reported but still are not sufficiently sensitive, specific 
and reliable for widespread practical application. The tight binding 
of THC to plasma protein (170) is only one of the many problems in 
the development of sensitive reliable tissue level assays (cf. Analytical 
Techniques, Detection). 

Cardiovascular effects 

Cannabis has long been known to have marked cardiovascular effects 
(21, 143). Last years report reviewed some preliminary data which 
resulted in some expressed concern about electrocardiographic changes 
during acute intoxication. The subsequent publication of a number 
of studies where cardiovascular dynamics were studied some time 
after administration of large doses of THC indicates that cannabis 
produces only minimal EKG changes in young healthy subjects (77. 
s. 22, 104) . Nonspecific P or T wave changes are most commonly noted. 
Occasional premature beats also occur. Tachycardia continues to be 
the most common and prominent physiological response to acute doses 
( 145). In a study of prolonged administration of oral doses of 30 mg 
delta-9-THC given every four hours, heart rate slowing and blood 
pressure drops developed (8). Blunting of peripheral vascular reflexes 
developed along with plasma volume expansion. Although tolerance 
developed to the orthostatic hypotension, the supine hypotensive 
effects persisted throughout the period of drug administration. These 
changes commonly seen in laboratory animals but not previously noted 
in man suggest a biphasic action of THC in humans with an increase 
in sympathetic activity involving the heart and peripheral blood 
vessels at low doses and a centrally mediated sympathetic inhibition 
at higher doses (65). The slightly increased supine blood pressure 
would be consistent with this mechanism (22, 77, 104). Forearm blood 
flow increases and total peripheral resistance decreases slightly with 
acute doses (104, 77) consistent with beta-adrenergic stimulation. The 
great individual variability in response to large intravenous doses has, 
however, led one group to suggest an indirect episodic activation of 
the sympathetic system secondary to psychological arousal in addition 
to the beta-adrenergic stimulation (104). Cardiovascular and ps} T cho- 
logical mechanisms of action may be independent as is suggested by 
the observation that DMHP, a synthetic cannabinoid. produces pro- 
found cardiovascular but few psychological effects (102). 

A series of reports on the cardiovascular effects on cannabis smok- 
ing in persons with coronary disease are consistent with the prelim- 
inary report cited last year (137, 4, 3). Smoking either marihuana or 
high nicotine cigarettes decreased exercise performance prior to the 
onset of angina, by increasing myocardial oxygen demand and decreas- 
ing myocardial oxygen delivery (4). Cardiovascular hemodynamics 
were evaluated by echocardiography (137). After marihuana, stroke 



78 

index decreased and ejection fraction was greater. Carboxyhemo- 
globin made for some changes after both marihuana and placebo. 
These studies demonstrate that marihuana eifects may differ in indi- 
viduals with pre-existing disease than in normals. Most research 
studies thus far have, of course, been done on youthful selected, normal 
volunteers. 

Pulmonary effects 

Because smoking is the most common means of cannabis consump- 
tion in this country, the effects of cannabinoids and marihuaa smoke on 
pulmonary function has been of continuing interest. The fourth Mari- 
huana and Health report described bronchodilating effects with pos- 
sible therapeutic implications after marihuana smoking. Previous 
reports have described mainly adverse findings in frequent chronic 
cannabis smokers including bronchitis, obstructive pulmonary defects, 
and chronic cough (62). 

Two groups publishing the promising reports described last year 
have continued and extended their studies (149, 156, 157, 168). Acute 
administration of either smoked marihuana or oral doses of THC 
produced statistically significant increases in bronchodilation and re- 
versed experimentally induced bronchospasm in young adults with 
bronchial asthma (156, 157, 168). Indications are that the mechanism 
is independent of beta adrenergic or antimuscarinic effects (149). In 
contrast to these promising reports, a British group (34, 58) found 
that measures of forced vital capacity, peak expiratory flow rate and 
other clinically useful measures of pulmonary function did not im- 
prove in a group of patients with reversible airway obstruction given 
10 mg doses of oral THC. One possible reason for these discrepant 
findings may be that the groups (149, 156) reporting cannabis-induced 
bronchodilation are using whole body plethysmography, an exceed- 
ingly sensitive measure that will detect very small changes in pul- 
monary function, whereas the less optimistic reports come from a group 
using less sensitive, although clinically relevant measurement 
techniques. 

Chronic smoking may produce different and less useful effects than 
acute administration as indicated by pulmonary function changes dur- 
ing periods of chronic administration (109). Mcndelson found signifi- 
cant impairments in pulmonary function tests (vital capacity, or FEY 
1.0) in a group of chronic marihuana smokers (109). Further reduc- 
tion in pulmonary function test performance developed during this 
study in which the volunteers smoked three to ten marihuana cigarettes 
daily for 21 days. An outpatient study of young adults with varying 
tobacco cigarette habits found more improvement in pulmonary func- 
tion during an eight week period of no smoking in the cannabis smoker 
subgroup (5). An invitro study suggests that the water soluble compo- 
nents of marihuana smoke may contain substances toxic to the defense 
network of the lung other than delta-D-TIK 1 or other cannabinoids 
(31). Studies using high doses of THC given intravenously noted only 
modest changes in minute ventilation and the ventilatory response to 
C02 equivalent to that produced by 5 mg doses of morphine (77, 10-1). 

A studv of the respiratory effects of smoked marihuana and orally 
ingested delta-9-THC has examined the effects of the drugs on the 
respiratory response curve. Both the synthetic and natural material 



79 

produced a respiratory depression in a group of previously chronic 
users. Although the effect was found to be slight, the authors recom- 
mend further study because of the possible relevance of this effect to 
patients with chronic lung disease or central nervous system impair- 
ment of respiratory regulation (172). 

Endocrine and metabolic effects 

The report of depressed plasma testosterone levels in chronic mari- 
huana smokers (98) and the report of a failure to find such a change 
in marihuana smokers receiving the drug daily over a 21-dav period 
(110) have led to further studies and discussion (55. 93, 96. 97", 99, 100, 
101). Kolodny has reviewed the numerous problems confounding the 
study of the hypothalamic-pituitary -testicular axis in man (96) and 
discusses possible biologic implications of lowered testosterone levels. 
He presents data (97, 100) showing significant drops in plasma tes- 
tosterone levels and luteinizing hormone levels two and three hours 
after smoking a single marihuana cigarette. In a chronic administra- 
tion study, subjects showed no significant drop in levels after four 
weeks of daily marihuana smoking; but. then, with continued smoking 
they had significant drops in luteinizing hormone, followed by falling 
testosterone levels and follicle stimulating hormone levels. Thus, the 
data from research finding no marihuana-related hormone changes 
(93, 110, 1-14) are quite consistent with studies that do (97, 98, 100) if 
the different time periods of marihuana use are taken into account. 
The biological significance of these changes is unclear and Kolodny is 
appropriately cautious in his interpretation of their importance (96). 
In most cases the plasma hormone levels remain within the usually 
accepted normal limits. Such alterations might be expected to be more 
important for prepubertal or pubertal males or males with already 
impaired sexual functioning. There might also be adverse effects on 
sexual differentiation of the fetus of mothers using cannabis. In the 
absence of clinical evidence for these consequences, such concern is at 
present speculative. 

One surgeon has attempted to link such hormonal changes to the 
development of gynecomastia in male marihuana users (66, 69). He 
was able to stimulate the development of rat breast tissue by delta-9- 
THC administration (66). Other investigators (101) have not found 
changes in serum prolactin levels in men given THC experimentally. 
The absence of prolactin changes is surprising since many centrally 
acting drugs alter prolactin levels. The reported gynecomastia was 
postulated to result from a prolactin dependent mechanism. 

In last year's report a study described glucose intolerance in a small 
group of subjects given intravenous doses of delta-9-THC (75). A 
lower dose of THC given a smoked hashish had no effect on blood 
glucose though blood lactic acid decreased (129). Glucose efflux from 
human erythrocytes was inhibited by THC and cannabidiol, suggest- 
ing some drug effects on glucose transport mechanisms (146) . It would, 
however, be quite speculative to try to relate these changes to the crav- 
ing for sweets often reported by cannabis users. 

Sexual functioning 

Reports discussed in the section on ''Endocrine Effects" describe sex 
hormone changes related to cannabis use. Although anecdotal accounts 



80 

describe cases of sexual dysfunction possibly associated with such 
changes, properly controlled studies are needed to confirm them (96, 
100). A number of accounts report enhanced sexual activity associated 
with cannabis use (11, 20, 51, 63, 93). However, the psychological, 
social and pharmacologic factors associated with sexual activity prob- 
ably interact in complicated ways as is true with most other drug effects 
on sexual behavior (20, 93). For example, with cannabis, as with alco- 
hol, dose is important. Small to moderate doses appear to be most effec- 
tive as releasers of inhibitions (93) . Larger doses and/or chronic use of 
marihuana may actually diminish sexual interest and potency in males. 
Adequate data elucidating the effect of marihuana use on sexual func- 
tioning are not yet available. 

Neurological effects 

Perceptual, cognitive and mood changes are presumably reflected in 
changes in nervous system activity. As with any psychoactive drug, 
however, simple one-to-one correlations between behavioral changes 
and brain activity are rare (78). The most important questions have 
to do with how long the effects persist : for hours, days, weeks or are 
they permanent? 

Most of the new studies are extensions of or attempts to replicate 
findings reported last year. Smoked cannabis produces acute, revers- 
ible, dose-related changes in brain waves as measured by computer- 
analyzed EEG (49, 91). Following ordinarily used doses, the changes 
are modest, consisting mostly of alpha wave slowing and are not in- 
dicative of any particular pathology. Cannabis does not appear to have 
unique qualities among CNS active drugs as measured by scalp EEGs. 
Changes in EEG recorded from deep brain structures, consisting of 
slow wave and spiking activity, have not, however, been seen with any 
other drug (67). These changes have been well-described in monkeys. 
Similar changes have been reported in a small number of humans (67) . 
The behavioral significance of these neurological changes is yet to be 
determined (78). A recent review of possible neural mechanisms of 
cannabis suggests the hippocampus and other deep structures may be 
important sites of action (41) , at least in animals. 

Scalp EEG and evoked potentials showed marked changes in sub- 
jects given very large smoked doses of THC or marihuana (158, 159). 
Alpha abundance increased with posterior slow wave activity becom- 
ing prominent. Ataxia, hypersomnia, increased deep tendon reflexes, 
tremor, tonic muscle contractions and myoclonus followed these 1 mg ' 
kg doses of THC. 

Loss of REM sleep appears to be a predictable effect of cannabis 
(158, 159). Total sleep time increases. Stage 4 or slow wave sleep is 
relatively unaffected. Tn this respect cannabis is unlike any sedative- 
hypnotic drug studied thus far (48). When the drug is stopped after 
a period of prolonged administration, I\EM sleep stage and eye move- 
ments show a marked rebound above baseline levels. Tn contrast to the 
relatively small changes in waking EEGs after the drug is given, sleep 
EEC changes are very dramatic and large — both when the drug is 
acutely and chronically administered (48) . 

Changes in the slow cortical potentials recorded from the scalp 
(contingent negative variation or CNV) after cannabis are of partial- 



SI 

lar interest since this measure is said to be sensitive to change- in 
motivation and attention deployment, among other factors. A recent 
study of the CNV obtained somewhat different results from those 
reported last year (10). Like many neurophysiology measures, it 
appears the CNV is far more complicated than was originally assumed. 
It appears the CNV may get larger or smaller after cannabis, depend- 
ing on the level of intoxication, the task demands, the motivation of 
the subject and changes in attention. To view the cannabis-induced 
CNV changes as any direct measure of attention deployment or moti- 
vation is probably an oversimplification (10). 

Effects on cell-mediated immune response 

Conflicting opinions as to the possible effects of cannabis on the 
cell-mediated immune response continue to appear (148) . In the fourth 
report, the observation that chronic marihuana users had decreased 
in vitro lymphocyte response to allogeneic cells and to a mitogen was 
described (118) . This original observation has led to extensive in vitro 
and animal studies described elsewhere in this report. Related studies 
in humans published this past year provide partial support for the 
notion of an immune system or thymus-derived cell alteration in 
people who smoke marihuana (30, 118, 134). However, other investi- 
gators using an in vivo skin testing procedure found no evidence of 
impairment of cell-mediated immunity in chronic marihuana users 
(151). Marihuana smokers had less T cell response to phytohemag- 
glutin stimulation and decreased PMN phagocytic capacity (134). 
The authors of the latter study caution that the clinical significance 
of these findings is uncertain. In possibly related in vivo studies, the 
white blood cells from both cannabis users and non-users showed simi- 
lar dose-related inhibition of migration when exposed to THC and 
extracts of cannabis (147). Substances other than THC in the crude 
extract may have effects on this test system. 

Administration of THC or cannabis to controlled populations, with 
before and after testing, is underway and may provide useful infor- 
mation in clarifying the etiology of the cell-mediated immune effects 
(125). 

Other physiologic effects 

Previous reports associated cannabis intoxication with decreases in 
intraocular pressure. The possible therapeutic implication of this unex- 
pected effect is discussed in the section on therapeutic applications. 
More extensive studies in normal volunteer subjects indicate a non- 
dose-related pressure drop lasting from four to five hours (68). The 
magnitude of the eye pressure decrease (about 30%) was the same 
whether the person smoked one or 22 marihuana cigarettes. Effects on 
other aspects of eye physiology (acuity, refractive error, biomicros- 
copy, fundus changes, visual fields, ophthalmodynamometry, electro- 
retinography and orthoptic evaluation) were minimal or absent. Other 
investigators concluded that the observed eye pressure decreases were 
more likely a consequence of drug-induced relaxation and sedation 
rather than specific cannabis effects on the eye, since other sedative 
drugs produced similar changes in eye pressure (52) . Results of studies 
of the effects of smoked marihuana on galvanic skin response are con- 
sistent with drug-induced reduction in level of autonomic nervous svs- 



82 

tern arousal (25) j However, recent findings seem to contradict this 
interpretation (cf. Therapeutic Aspects). 

Intravenous administration of a water infusion of cannabis resulted 
in gastroenteritis, hypoalbuminemia, hepatitis, and many cardiovascu- 
lar changes secondary in part to hypovolemia (131). It is not entirely 
clear what symptoms were cannabinoid effects or, more likely, the non- 
specific effects of injected foreign plant material. 

Acute effects on mental and psychomotor pei'formance 

As in previous years a host of studies have reported impaired func- 
tioning on a variety of cognitive and performance tasks while mari- 
huana intoxicated. For the most part, impairments were dose-related. 
The investigators who gave the smallest doses generally reported the 
fewest effects. Impaired memory (9, 33, 38, 39, 167), altered time sense 
(9, 167) and decrements on performance on a number of tasks — such 
as those involving reaction time, concept formation, learning, percep- 
tual motor coordination, attention and signal detection — are commonlv 
described (9, 24, 25, 32, 35, 37, 115, 116, 119, 120, 121, 150, 162). A 
number of discussions of the locus of the memory impairment have 
appeared (33, 39, 164). There is a growing consensus that the memory 
defect is due to a storage problem rather than acquisition or retrieval. 
There has been concern that cannabis may increase the suggestibility 
of those using it. However, in laboratory studies marihuana smoking 
had no effect on hypnotic susceptibility (6) . 

Effects on sensory function 

One of the more commonly reported effects of cannabis is a sub- 
jective change in sensation. A number of groups investigated drug 
effects on various aspects of sensory functioning. Although subjective 
impressions of changes in skin sensitivity are commonly associated 
with cannabis intoxication, no objective or measurable change in 
cutaneous sensitivity using a number of measures was noted (115). 
The decrease in auditory signal detection while intoxicated appeared 
to be due to a decrease in sensitivity rather than a change in criteria 
(120). This finding contrasts with the usual subjective reports of en- 
hanced auditory sensitivity. THC given to patients sufferine: from 
pain demonstrated mild analgesic effects but 20 mg doses orally pro- 
duced many unpleasant side effects — somnolence, dizziness, ataxia, 
blurred vision, etc. (126. 127). The experience of experimentally in- 
duced pain in normal subjects was also diminished by smoked mari- 
huana (130). Pain secondary to spinal cord injury was decreased by 
cannabis use (42). The characteristics of preferred tone frequency 
were shifted while intoxicated (35). 

Automobile driving performance 

More evidence has accumulated indicating that driving ability and 
rel tted skills arc 1 impaired bv cannabis at doses likely to be commonlv 
used in the United Slates (90. 89. 119, 44). Despite their commonlv 
expressed belief that their driving ability is impaired when intoxicated 
(90, 1C>.°>, 32), more cannabis users appear to drive today while intoxi- 
cated than was the case a few years ago. In limited survevs C)Q% to 80% 
of the users questioned reported driving soon after marihuana use (90, 
154). The use of alcohol in combination with marihuana before driv- 



ing was reported by 64% of one sample and during driving by 20% 
of the sample (90). As the risks of arrest for possession decrease, one 
might expect more users will take the chance of being caught while 
intoxicated and driving (154). 

A more detailed report of a Canadian driving study discussed last 
year (89) has appeared (90). The data clearly demonstrate that mari- 
huana in relatively low doses (cigarettes containing approximately 5 
and 8 mg of THC) typically had a detrimental effect on driving skills 
and performance not only on a test course but also under more usual 
city driving conditions. However, as is true with alcohol, effects were 
not uniform with all drivers. Some, particularly at the lower dose, 
actually improved their performance. Thus, the problem of individual 
differences that has complicated developing and enforcing "drunk 
driving" laws will probably recur when discussions of the minimal 
allowable dose or blood level of cannabinoids come up. 

Compared to most of the behavioral tasks studied in the laboratorv, 
automobile driving is more complex. The relative importance of the 
various perceptual, cognitive and psychomotor functions in determin- 
ing driving ability is not completely understood. For example, in some 
situations the cognitive impairment produced b} T cannabis may have 
only limited impact on actual driving performance due to concomitant 
drug-induced changes in risk acceptance or feelings of aggression. In 
a laboratory simulation of driving, cannabis-intoxicated subjects took 
longer to decide whether to pass another car seemed less likely to accept 
the risks of passing and seemed less aggressive than alcohol-intoxicated 
subjects (40, 45). Other laboratory simulator studies have found that, 
while some driving skills are relatively unaffected by marihuana, there 
is a dose-related impairment in the ability to attend to peripheral 
stimuli while driving (119). Such an impairment might interfere with 
a driver's response to a car suddenly emerging from a side street. 

Because of the many inherent inadequacies of laboratory driving 
simulator studies (90), cannabis-related driving risks will ultimately 
have to be assessed on the basis of studies of actual accident rates for 
users compared to non-users. This has been difficult in the study of 
alcohol. It promises to be still more difficult with cannabis because of 
the difficulties of measuring tissue levels of the cannabinoids, the 
longer excretion times, the more complicated metabolism and the often 
combined use of cannabis and alcohol while driving, making the rela- 
tive contribution of either drug uncertain (90, 154) . 

Flying an airplane demands still more complex skills than does 
driving. There is little information concerning possible pilot error 
or impairment in performance as a result of having used marihuana. 
A preliminary study has shown that under flight simulator test con- 
ditions experienced pilots showed marked deterioration in perform- 
ance following smoking marihuana containing 6 mg. of THC (108). 
More detailed studies are planned to follow up these initial 
observations. 

X on pharmacologic determinants of subjective response 

Sociocultural factors (128) appear to interact with such pharma- 
cologic aspects as dose and route of administration so as to modify 
marihuana's subjective effects. Some of these factors were explored in 



84 

studies published this past year. Laboratory studies are often criticized 
because a sterile, scientific laboratory setting may alter the response 
to the drug so that findings have little relevance to more typical con- 
ditions of use. A group of subjects were randomly assigned to smoke 
marihuana (16 mg THC) and were tested either in a typical medical 
research laboratory or a private living room designed to facilitate a 
pleasurable drug experience (76). Although there were great differ- 
ences between subjects in their subjective responses to the smoked 
marihuana, the effect of the very different settings was negligible. 
A similar study using only a subjective level of intoxication as an 
index of drug effects found a psychedelic environment was associated 
with greater intoxication at intermediate dose levels, but not at the 
highest (16 mg THC) dose employed (14). Another attribute of the 
setting in which cannabis is often used is the possible effect of other 
intoxicated friends on a person's "high." However, in a study testing 
the effects of modeling, subjects smoking marihuana for the first time 
were relatively unaffected by the presence of an actor modeling a 
marihuana high (17). The results of this study suggest that previous 
experience with cannabis is a complicated socialization process in 
which individuals learn from friends and others to discriminate and 
label various aspects of the drug state (17) . The mood one is in before 
smoking is sometimes thought to interact with the drug effects to 
produce varied outcomes. A laboratory study found no difference in 
subjective response to low doses of smoked marihuana and no difference 
in level of anxiet}^ in groups of subjects made anxious by exposure to 
laboratory stresses (136). Finally, in a study mentioned in last year's 
report, but which had not yet been published, it was found that the 
dose of cannabis consumed in an experimental laboratory setting was 
determined by many factors (size of cigarettes, past drug experience) 
other than pharmacologic potency of the drug (15). A similar study 
by the same group (14) found that controlling the amount of drug 
consumed in accord with its varying strength was difficult for subjects, 
again suggesting that nonpharmacologic considerations are important 
in affecting the amounts consumed. 

CANNABIS AND PSYCIIOPATHOLOGT 

The association of cannabis use with psychiatric illness raises com- 
plex questions for which no completely satisfactory answers are yet 
available. Two reviews of past research point out the many methodol- 
ogical and theoretical shortcomings of existing work (64, 112). A 
variety of psychiatric disorders are clearly associated with the use of 
cannabis — however, whether the psychopathology is an antecedent to 
use, a consequence or a mere coincidence is still very much open to 
question. A best guess is that cannabis use like that of many other 
psychoactive drugs will sometimes be an antecedent, a consequence or 
coincidental to psychopathology, depending on the person and many 
other variables (112). 

As is often true in medicine, the ambiguity in diagnostic classifica- 
tion and definition adds to the confusion concerning adverse psycho- 
logical reactions associated with cannabis use. The following classifi- 
cal ion has been adopted in imposing some order on the literature (64, 
112). 



85 

Acute panic anxiety reactions 

The acute panic anxiety reaction has been noted by many reviewers 
to be the most common adverse reaction to cannabis use (64, 112) , The 
symptoms and signs are usually exaggerations of normal cannabis 
effects more generally described by users. Anxiety is often focused on 
fears of "going crazy." This reaction appears most likely to occur in 
novices and after consuming more potent materials. Personality vari- 
ables that make for poorer coping skills play a role. The symptoms 
diminish with authoritative reassurance or in a few hours when the 
immediate drug effects have worn off. A number of reports in the past 
year illustrate these considerations (1, 87, 117, 124, 127, 164. 166). 

Patients with chronic pain (127) and depression (1,139) given low 
doses of THC in therapeutic trials had far more dysphoric and acute 
panic episodes than would be expected if the same doses were given 
to typically youthful cannabis users. These older people presumably 
found it difficult to accept the drug-induced mental changes as desir- 
able. Younger but equally inexperienced "cannabis experimenters" 
often react similarly (164, 117). 

Cannabis-induced mild paranoid feelings in student and "counter 
culture" users of marihuana are common and usually not a source of 
undue concern to them (87). About two-thirds of a student group and 
95% of a counter culture group studied described suspicion of being- 
subjected to a police raid or having friends tricking them while intoxi- 
cated. Inability to reality test concerning these suspicions was reported 
by over half of the subjects. Another field survey found that indi- 
viduals with a tendency to use paranoid defense mechanisms experi- 
enced fewer acute anxiety reactions after cannabis (124). The authors 
thought that the more sophisticated defenses represented in paranoid 
functioning may be effective in preventing acute adverse reactions. The 
same study found that persons with high scores on the schizophrenia 
subscale of the MMPI tended to have more problems with adverse 
psychological reactions indicating (as have a host of previous studies) 
that pre-existing psychopathology is an important factor in such 
reactions. 

Can nobis induced acute-brain syndrome or toxic delirium 

The clinical features of the acute brain syndrome associated with 
cannabis intoxication — such as clouding of mental processes, disorien- 
tation, confusion and marked memory impairment — are similar to 
those produced by other exogenous toxins (64, 112). The syndrome is 
most likely to occur at high doses and to be dose-related, whereas the 
panic reactions may occur at any dose unfamiliar to the user (64, 112, 
79) . The toxic delirium is likely "to follow the time course of other drug 
effects. This syndrome appears to be relatively rare in the United 
States. 

Prolonged reactions 

Possible prolonged psychological effects of cannabis use are an area 
of serious concern and controversy. These include not only psychic 
reactions but also personality change, change in life style, a possible 
"amotivatiohal syndrome," "flashbacks" and a possible causal rela- 
tionship between marihuana use and use of other drugs. Here it is 



86 

even more difficult to establish precise cause and effect because the close 
relationship between ingestion of the drug and acute effects is lacking. 

Descriptions of a specific long lasting cannabis psychosis appear 
largely in the Eastern literature, and thus are largely drawn from 
a culture where use is generally more frequent, and at higher dose 
levels, than normally is typical for the United States. This acute 
"cannabis psychosis" is generally associated with very frequent use 
and reportedly lasts one to six weeks or longer (64, 112) . Recent studies 
abroad in Jamaica (141), Greece (155) or Costa Rica (23) where 
frequent users of high potency cannabis were examined failed to docu- 
ment the existence of a specific cannabis psychosis. However, small 
sample sizes were involved and such a relatively rare occurrence could 
well have been missed. 

A few years ago a clinical report b} T Kolansky and Moore (95) 
described eight psychotic reactions in a group of 39 marihuana 
smokers in this country and attempted to demonstrate a eause-and- 
effect relationship to their marihuana use. A more recent clinical study 
demonstrates how correlations between various behaviors and subse- 
quent psychiatric disorders can be misleading (2). Consecutive first 
admissions to a psychiatric hospital were evaluated. Thirty-eight 
patients who had used marihuana prior to the onset of psychiatric 
problems were studied. Indeed, apathy, poor judgment, confusion and 
depression followed marihuana smoking, but the correlations between 
marihuana use and subsequent illness was less than with such causally 
unrelated variables as having masturbated, having experienced sex 
education, and having drunk beer. In this clinical study marihuana 
use could not be singled out as a prime factor leading to psychiatric 
illness. 

Marihuana flashbacks — spontaneous recurrences of feelings and per- 
ceptions similar to those produced by the drug — continue to be re- 
ported (12) . The etiology of such flashbacks remains obscure, but those 
who experienced them seem to require minimal treatment, if any. 

Now psychotic prolonged adverse reactions 

Surveys of user and non-user populations provide some information 
as to nouromvcholotncal changes, changes in life stvle and the so-called 
amotiyational syndrome associated bv some with cannabis use. In 
an all too vw^ prospective study. Culver and King (28) compared 
groups of T,SD-mescalin° users with marihnana-hashish users and 
no'i-driujr using controls. The hivostigators used a sophisticated narco- 
logical test battery includhur the Halsted-Reitan tests, the Wechsler 
Adult Intelligence Scale and tests of spatial perceptual abilities. When 
tested a year later the LSD-mescal i no group scored least well on the 
trail makinir tost but the performance of all three groups fell within 
normal limits. No evidence conld be found for the existence of a neuro- 
psychological deficit with either light or frequent caimabis use. 
Another study of heavy drug users using a similar test battery arrived 
at similar conclusions (V\). However, the authors of the study remind 
their readers that one should not conclude that no organic changes 
occurred since psychological test data is inferential and definitive 
statements as to organic changes can only be based on radiological or 
pathological evidence. One study of multiple drug users in the Navy 
found a large number of psychiatric symptoms reported by them on 



87 

the Cornell Medical Index but because of the variety of drugs habit- 
ually used it was impossible to single out marihuana use as an impor- 
tant factor (61). 

The possible effects of cannabis on student performance has been a 
major concern because of the extensive use by that group. A longitudi- 
nal study of a sample of 1.9T0 college students examined the relation- 
ship between cannabis use and psychosocial adaptation and academic 
performance (11). Users and non-users did not differ in grade point 
ave rage or in educational achievement, but the marihuana users seemed 
to have more difficulty in deciding on career goals and dropped out of 
college more often to reassess goals. A smaller percentage of regular 
users planned to seek advanced or professional degrees. There was, in 
the opinion of the users themselves, a poorer academic adjustment 
among the most frequent users than among infrequent or non-users. 
Only 6% of non-users reported a worsening of their emotional state 
since beginning college but 20% of the long duration users reported 
negative changes in emotional state. A problem with the study was 
that a significant percentage of the initial sample was lost over the 
three year period. If the loss was from the group who failed out or 
dropped out, those most likely to show loss of motivation or intellec- 
tual functions may have been automatically excluded from the study. 
Also, the study merely reported the students' own assessment of their 
adaptation since no interviews were attempted. Other questionnaire 
surveys reported differences between users and non-users but the ques- 
tion of causation remains and the mental health significance of some 
of the findings are unclear. Non-users scored higher on needs for 
achievement and order and not surprisingly had higher grades (152). 
Other surveys found marihuana users to be more dissatisfied, disillu- 
sioned and alienated (29), more oriented towards the past (88), but 
to be more creative and adventuresome (60) . They also had lower levels 
of achievement (16). 

The ability of cannabis users to work in other contexts has been 
examined in attempts to see if a measurable "amotivational syndrome" 
exists (113, 111). In a study of frequent and infrequent users smoking 
cannabis while living on a research ward, work output decreased as 
marihuana consumption increased (111), However, the investigators 
noted that "motivation'' is a function of situational variables as well 
as drug factors. To term the decrement in work output "amotivational" 
would imply that the users in the experiment had lost interest in work- 
ing for money. However, if the work decrement resulted from a drug- 
induced impairment of performance, it would not be proper to term it 
a motivation effect. In a similar Canadian study (113) a fall in pro- 
ductivity (making stools) followed the smoking of cannabis. The 
decreased productivity appeared to be due to less time spent working 
rather than to decreased efficiency. The authors interpret this as indica- 
tive of an "amotivational syndrome." To the extent that these types of 
studies involve artificial work conditions and tasks dissimilar to more 
usual employment, it is hazardous to draw more general conclusions 
regarding the role of cannabis in a more generalized amotivational 
picture. Moreover, these studies involved intensive daih T use. Their 
relationship to episodic or less frequent use in altering motivation is 
unknown. 



88 

An assumed relationship between cannabis use and the use of other 
drugs (mainly opiates) has been a source of concern. The progression 
hypothesis is a good example of a theoretical construct repeated so 
many times that it has become verified by repetition rather than by 
facts (161). The patterns of the shifts from one drug to another seem 
to be changing with more of a "progression" to "polydrugs" other than 
heroin (57). In a military population the pattern of drug use and 
selection of drugs was determined more by availability, peer pressure 
and drug use fads than by pharmacologic or personality variables 
(123). Cannabis users are, however, very likely to use other licit and 
illicit drugs with a positive correlation between level of cannabis use 
and the variety of drugs used ( 122) . 

Criminal and aggressive behavior 

The often discussed possible link between cannabis use and crime 
or aggressive behavior was the topic of reviews (56, 92) and experi- 
mental studies (26, 107, 142). Both reviews (56, 92) concluded that 
evidence showing marihuana to cause crime is virtually nonexistent. 
Young prisoners who varied in their degree of marihuana use were 
compared using a number of personality measures (e.g., MMPI, CPI) 
(107). Non-users and occasional users had typical criminal profiles. 
Regular users of only marihuana were better socialized and adjusted, 
though more deviant, than collegiate marihuana users. Prisoners who 
used marihuana plus other drugs were the most deviant. 

In addition to concern about marihuana use and criminality, the 
association between marihuana intoxication and hostile human be- 
havior has been a topic of great interest and discussion. The results of 
observations and self -reports of hostile, aggressive feelings from re- 
search subjects intoxicated acutely or chronically with cannabis sug- 
gest the usual effects are to decrease expressed and experienced hos- 
tility (80,109,142). 

CHRONIC EFFECTS 

Tolerance 

Marked tolerance to the effects of cannabis doses commonly con- 
sumed in this country is not usually evident, presumably because of 
relatively infrequent use and the generally low doses of active mate- 
rial. However, as data accumulate from countries where more frequent 
use of high doses is common (23, 49, 141, 155), it is apparent that tol- 
erance must develop to many of the psychological and physiological 
effects. In controlled experimental situations where prolonged admin- 
istration of THC or marihuana to volunteer subjects has been under- 
taken, what appears to be dose-related tolerance develops rapidly (8. 
53, 80, 109, 111) as judged by behavioral, psychologic and physiologic 
measures. 

In outpatient studies where frequent and infrequent users or other 
populations with differing drug histories are compared in their re- 
sponse to a given dose of cannabis, the results are less consistent. 
Marked tolerance to measured effects is rarely obvious, if evident at 
all (94, 132, 1 W, 155). However, when sensitive and reliable measures 
are used, even infrequent use may produce evidence of some. degree 
of tolerance on outpatient laboratory tests (9, 24). Tolerance in man 
is apparently a dose-related effect as it is in animals (36). 



89 

Dependence 

When volunteers were given 30 mg closes of THC orally for 10-20 
days, sudden cessation of the drug was associated with the appearance 
of irritability, restlessness, decreased appetite, marked sleep disturb- 
ance (including sleep EEG alterations), sweating, salivation, tremor, 
weight loss, nausea and vomiting, diarrhea and, in general, a clinical 
picture similar to that following chronic administration and moderate 
doses of many sedative-hypnotic drugs (8, 48, 80). Such psychologic 
and physiologic changes have not been commonly observed in other 
chronic administration studies in this country. Restlessness and weight 
loss was reported by Mendelson in an inpatient volunteer study at the 
end of a 21-day smoking period (109). Drug-seeking behavior has not 
been associated with the withdrawal syndrome, but the presence or 
absence of such behavior is difficult to assess in the laboratory. A with- 
drawal syndrome has not been described in recent investigations of 
chronic users abroad (23, 49, 141). 

Field studies of chronic users 

Several field studies of populations of frequent loug-term users have 
searched for possible adverse or other effects associated with chronic 
use (23. 49, 94, 141). These all were concerned with user in countries 
whore high potency cannabis is more readily available than in the 
United States. 

The results of a chronic user study discussed in two previous reports 
were recently published in book form (141) . The 30 experimental sub- 
jects had been smoking high potency cannabis almost daily for ten 
years or more. Few psychological or physiological differences between 
the cannabis smokers and nonsmokers were evident. There was no 
evidence for liver, kidney or cardiovascular malfunction. While no 
differences in chromosomal abnormalities were found, the results must 
be regarded as inconclusive because of various technical deficiencies 
of the study. Modest decreases in pulmonary function and altered 
hemoglobin levels were the only physiologic differences evident. The 
impact on these findings of tobacco use by the subjects is uncertain. 
After smoking cannabis, a small group of workers produced less work 
(weeding, hoeing, digging) with more movements, but otherwise 
showed no evidence of "amotivation." The importance of cultural 
differences in the interpretation of drug effects is evident in that people 
in Jamaica did not find th^ir appetite increased by cannabis, nor their 
hearing enhanced nor their (ime sense altered, and in fact said they 
used cannabis so as to work better. Although reassuring, the findings 
should also be judged in perspective. They were derived from a small 
group of selected users, so that rare consequences (if thev did occur) 
suoh as brain atrophy or psvchosis might not have been detected. The 
subjects were laborers and farmers in a very different culture, so that 
intollecual impairment may have been relatively difficult to detect. 

A similar although larger and more complex study is underway in 
Costa Eica. Coggins presented a preliminary report (23). Eighty 
dailv marihuana users and matched noncannabis-using controls were 
ovaluated with extensive medical examinations, laboratory studies. 
X-rays, EEG, EKG and neuropsychological testing. Although the 



ttf,2- 



90 

study is still in progress, no evidence for a greater incidence of disease 
or deterioration has yet to be found. 

In studies of Greek and chronic hashish users approximately 47 
chronic users were compared with 40 control nonusers on a variety 
of EEG, echoencephalographic, neuropsychologic and experimental 
laboratory tests (49, 94, 155). Conventional clinical measures of brain 
damage (EEG, echo-EEG) showed no evidence of abnormality in the 
chronic users. Tolerance to administered doses rapidly developed on 
the EEG indices. No evidence of withdrawal symptoms after three 
days of chronic administration was evident. When given high doses 
of THC, some of these very experienced subjects developed unpleasant 
psychological symptoms when their tolerance level was exceeded. 
These were all outpatients so no precise control over drug use outside 
of the laboratory was possible. A slightly higher incidence of per- 
sonality disorders in the hashish-using group was better explained by 
psychosocial variables than by marihuana use. 

Thus, these three field studies of users abroad do not report brain 
damage, psychosis or an "amotivational syndrome." However, the 
cultures are different, and the sample populations are relatively small 
so such drug effects can not be ruled out. They may be simply uncom- 
mon or difficult to measure. 

Chronic effects — laboratory studies 

A number of groups have studied the effects of daily cannabis use 
in paid volunteer subjects consuming cannabis for up to 72-day periods 
while hospitalized (8, 48, 53, 80, 109, 111, 113). Although even 72 days 
is not really chronic use. such studies complement the more commonly 
performed acute outpatient studies. In general, in all these chronic 
or subchronic studies, subjects have tolerated the drug treatment phase 
well and very few dropouts, psychoses, or other blatant manifestations 
of distress were revealed. Except for the pulmonary function changes 
noted in one study (109), drug effects on mental, behavioral and 
physiologic functions appear to disappear rapidly on cessation of 
drug administration and have been, in general, similar to those seen 
in acute studies. Tolerance is evident at lower doses (53, 109) and 
obvious at high doses (80). 

Adverse physiologic effects associated ivith chronic use 

Mention has already been made of the endocrine and immunologic 
changes reported in some populations of users. Mutagenesis and terato- 
genesis is discussed elsewhere in this report. A discussion of the report 
of brain ventricle changes was presented in a previous report. A paper 
describing the same group of subjects appeared this past year (46), 
but no similar reports have yet appeared. The difficulty of performing 
pneumoencephalograms in neurologically normal volunteers makes 
survey studies impossible. A number of groups are testing cannabis 
users with noninvasive techniques for measuring brain ventricle size 
(computerized tomography) and preliminary results should be avail- 
able soon, An investigator who reported the electrical ehangcs in the 
deep brain structures of a human smoking marihuana has now com- 
pleted chronic studies in monkeys, finding similar electrical changes. 
The slow wave activity persists for months after the cessation of a 
chronic period of smoking. The behavioral and biological significance 
of the changes in man is uncertain. 



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75. Hollister, L. E. and Reaven, G.M. Delta-9-tetrahydrocannabinol and glucose 
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89. Klonoff, H. Marijuana and driving in real-life situations. "Science.' - 1M>: 
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90. Klonoff, H. Effects of marijuana on driving in a restricted area end on 
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108. Meacham, M. P., Janowsky, D. S., Blaine, J. D., Bozzetti, L. P., Jr. and 
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109. Mendelson, J. H., Rossi, A. M. and Meyer, R. E. (Eds.) "The Use of 
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110. Mendelson, J. H., Kuehnle, J., Ellingboe, J. and Babor, T. F. Plasma 
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111. Mendelson, J. H., Kuehnle, J. C, Greenberg, I. and Mello, N. K. Marihuana, 
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112. Meyer, R. E. Psychiatric consequences of marihuana use : The state of the 
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113. Miles. C. G., Congreve, G. R. S., Gibbins, R. J., Marshman, J., Devenyi. P. 
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114. Miller, L. L. (Ed.) "Marijuana. Effects on Human Behavior." New York: 
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115. Milstein, S. L., MacCannell, K. L.. Karr, G. and Clark, S. Marijuana-pro- 
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116. Milstein, S. L., MacCannell, K., Karr, G. and Clark, S. Marijuana-pro- 
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161 (1) : 26-31 (1975). 

117. Mirin, S. M. and McKenna, G. J. Combat zone adjustment: The role of 
marijuana use. "Military Medicine," 140 (7) ; 482-485 (1975). 

118. Morishima, A. and Nahas, G. G. Effects of cannabinoids on replication of 
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119. Moskowitz, H., McGlothlin, W. and Hulbert, S. "The Effects of Marilmann 
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120. Moskowitz, H. and McGlothlin, W. Effects of marihuana on auditory 
signal detection. "Psychopharmacologia," 40 (2) : 137-145 (1974). 

121. Moskowitz, H.. Shea. R and Burns, M. Effect of marihuana on the psycho- 
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122. Mullins, C. J., Vitola, B. M. and Michelson, A. E. Variables related to 
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124. Naditch, M. P. Acute adverse reactions to psychoactive drugs, drug usage, 
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125. Nichols, W. W., Miller, R. C, Heneen, W., Bradt, C, Hollister. L. and 
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126. Noyes, R., Jr., Brunk, S. F., Baram, D. A. and Canter, A. Analgesic effect of 
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127. Noyes, R., Jr., Brunk, S. F., Avery, D. H. and Canter, A. The analgesic 
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128. Orcutt, J. D. and Biggs, D. A. Recreational effects of marijuana and alco- 
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129. Papadakis, D. P., Michael, C. M., Kephalas, T. A. and Miras. C. J. Effects 
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130. Payer, L. Marijuana increases pain tolerance. "The Journal" (Addiction 
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131. Payne, R. J. and Brand, S. N. The toxicity of intravenously used mari- 
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132. Perez-Reyes, M., Timmons, M. C. and Wall, M. E. Long-term use marijuana 
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133. Perez-Reyes, M., Wagner, D., Brine, D.. Christensen, H. D. and Wall. M. E. 
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134. Petersen, B. H., Graham, J., Lemberger, L. and Da Iron, B. Studies of the 
immune response in chronic marihuana smokers. "Pharmacologist," 16 (2) : 259 
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135. Pillard, R. C. Marihuana is not a public health menace: It is time to relax 
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13& Pillard. R. <\ MeXair, D. M. and Fisher. S. Does marijuana enhance 
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137. Prakash, R., Aronow. W. S., Warren. M., Laverty, W. and Gottschalk, L. A. 
Effects of marihuana and placebo marihuana smoking on hemodynamics in 
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13ft. Pryor. <;. T. Acute and subacute behavioral and pharmacological inter- 
actions of delta 9 TIP ' with other drugs. "Pharmacology of Marihuana." Edited 
by Szara. S. and Brail de, M. New York : Haven Tress (in press). 

139. Regelson, \\\. Butler, 4. B., Schnltz, J., Kirk, T., Peek, L. and Green. M. L. 
Delta-!) tetrahydrocannabinol ( delta -&-THC) as an effective anti-depressant 



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and appetite-stimulating agent in advanced cancer patients. "Pharmacology of 
Marihuana." Edited by Szara, S. and Braude, M. New York: Raven Press (in 
press). 

140. Renault, P. F., Schuster, C. R., Freedman, D. X., Sikic, B., de Mello, D. N. 
and Halaris, A. Repeat administration of marihuana smoke to humans. "Archives 
of General Psychiatry," 31 : 95-102 (1974). 

141. Rubin, V. and Comitas, L. "Ganja in Jamaica : A Medical Anthropological 
Study of Chronic Marihuana Use." The Hague : Mouton, 1975. 

142. Salzman, C, Van Der Kolk, B. A. and Shader, R. I. Marijuana and hostility 
in a small group setting. Presented at the American Psychiatric Association Meet- 
ing, 1975. 

143. Savary, P., Laureuceau, J. L., De Lean, A., Roy, P. and Marquis, Y. Acute 
cardiovascular effects of inhaled cannabis sativa smoke in man. "International 
Journal of Clinical Pharmacology, Therapy and Toxicology." 10(2) : 150 (1974). 

144. Schaefer, C. F., Gunn, C. G. and Dubowski, K. M. Normal plasma testo- 
sterone concentrations after marihuana smoking. "New England Journal of Medi- 
cine," 292(16) : 867-868 (1975). 

145. Schaefer, C. F„ Gunn, C. G. and Dubowski, K. M. Marihuana dosage control 
through heart rate. "New England Journal of Medicine," 293(2) : 101 (1975). 

146. Schurr, A., Sheffer, N., Graziani, Y. and Livne, A. Inhibition of glucose 
efflux from human erythrocytes by hashish components. "Biochemical Pharma- 
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147. Schwartzfarb, L., Needle, M. and Chavez-Chase. M. Dose- related inhibition 
of leukocyte migration by marihuana and delta-9-tetrahydrocannabinol (THC) 
in vitro. "Journal of Clinical Pharmacology," 14(1) : 35-41 (1974). 

148. Segelman, A. B., Segelman, F. P., Nahas, G. G., Suciu-Foca, N., De Soize, B., 
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munity in marihuana smokers. "Science," 185(4150) : 543-544 (1974). 

149. Shapiro, B. J. and Tashkin, D. P. Effects of beta-adrenergic blockage and 
muscarinic stimulation upon cannabis bronchodilation. "Pharmacology of Mari- 
huana." Edited by Szara. S. and Braude. M. New York: Raven Press (in press). 

150. Sharma, S. and Moskowitz, II. Effects of two levels of attention demand 
on vigilance performance under marihuana. "Perceptual and Motor Skills," 38(3, 
Parti) : 967-970 (1974). 

151. Silverstein, M. J. and Lessin, P. J. DNCB skin testing in chronic mari- 
juana users. "Pharmacology of Marihuana." Edited by Szara, S. and Braude, M. 
New York : Raven Press (in press) . 

152. Simon, W. E. Psychological needs, academic achievement and marijuana 
consumption. "Journal of Clinical Psychology," 30(4) : 496-498 (1974). 

153. Simon, W. E., Simon, M. G., Primavera, L. H. and Orndoff, R. K. A com- 
parison of marijuana users and nonusers on a number of personality variables. 
"Journal of Consulting and Clinical Psychology," 42(6) : 917-918 (1974). 

154. Smart, R. G. Marihuana and driving risk among college students. "Journal 
of Safety Research," 6(4) : 155-158 (1974). 

155. Stefanis, C, Boulougouris, J. and Liakos, A. Clinical and psychophysio- 
logical effects of cannabis in long term users. "Pharmacology of Marihuana." 
Edited by Szara, S. and Braude, M. New York: Raven Press (in press). 

156. Tashkin, D. P., Shapiro, G. J. and Frank, I. M. Acute bronchial effects of 
smoked marijuana (MJ) and oral delta-9-tetrahydrocannabinol (THC) in asth- 
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157. Tashkin, D. P., Shapiro, B. J. and Frank, I. M. Acute effects of marijuana 
on airway dynamics in spontaneous and experimentally induced bronchial asthma. 
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Raven Press (in press). 

158. Tassinari, C. A., Peraita-Adrados, M. R., Ambrosetto, G. and Gastaut, H. 
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159. Tassinari, C. A., Ambrosetto, G. and Gastaut, H. Clinical and polygraphic 
studies during wakefulness and sleep of high doses of marihuana and delta-9- 
THC in man. "Pharmacology of Marihuana." Edited by Szara, S. and Braude, M. 
New York : Raven Press (in press) . 

160. Teale, J. D., King. L. J.. Forman, E. J. and Marks. V. Radioimmunoassay 
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162. Thoden, J. S., Mosher, R., MacConaill, M. and Ling, G. Effects of mari- 
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163. Thompson, P. "Stoned" driving is unpleasant, say marijuana smokers. 
"The Journal" (Addiction Research Foundation, Toronto), 4(1) : 13 (1975). 

164. Tinklenherg, J. R. and Darley, C. F. A model of marihuana's cognitive 
effects. "Pharmacology of Marihuana." Edited by Szara, S. and Braude, M. New 
York : Raven Press (in press). 

165. Turner, C. E. and Henry, J. T. Constituents of cannabis sativa L. IX: 
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166. Tylden, E. The clinical features of cannabis use. "Practitioner," 212(1272) : 
810-814 (1974). 

167. Vachon, L., Sulkowski, A. and Rich, E. Marihuana effects on learning, 
attention and time estimation. "Psychopharmacologia," 39(1) : 1-11 (1974). 

168. Vachon, L., Mikus, P., Morrissey, W., Fitzgerald, M. and Gaensler, E. 
Bronchial effects of marihuana smoke in asthma. "Pharmacology of Marihuana," 
Edited by Szara, S. and Braude, M. New York: Raven Press (in press). 

169. Wall, M. E., Brine, D. R. and Perez-Reyes, M. Metabolism of cannabinoids 
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York : Raven Press (in press). 

170. Widman, M., Agurell, S., Ehrnebo, M. and Jones, G. Binding of (plus)- 
and ( minus ) -delta-1-tetrahydrocannabinols and (minus) -7-hydroxy-delta-l-tetra- 
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171. Hembree, W. Effects of marihuana on gonadal function in man. Paper 
presented at the Satellite Symposium on Marihuana of the Sixth International 
Congress of Pharmacology, Helsinki, Finland, July 26-27, 1975. 

172. Bellville, J. W., Swanson, G. D. and Kamel, A. A. Respiratory effects of 
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541-548 (1975). 



CHAPTER 8 

Effects of Marihuana ox the Genetic and Immune Systems 

The effects of marihuana and other cannabis preparations on the 
genetic and immune systems have recently been areas of intensive 
research. Since the fourth Marihuana and Health report, a wealth of 
new information has become available. 

ANIMAL STUDIES 

In the area of preclinical investigations, chromosome studies in 
rats and hamsters have been negative (23, 35). However, cytological 
and cytochemical studies of hamster lung cultures (18) exposed to 
smoke from marihuana and tobacco cigarettes found an inhibition 
of DNA synthesis and cell division, abnormalities in mitosis, and 
variable DXA content in chromosomes. Recently. THC was found to 
reduce the number of lymphocytes and leukocytes and inhibit the 
hemolytic plaque forming cell response (a measure of antibody pro- 
ducing cells) in mouse spleens (16). In another study (13), an increase 
in lymphocytes in rat bone marrow accompanied inhibition of 
myelopoiesis following administration of delta-9-THC. There is also 
the report by Harris et. al. (11) that delta-9-THC administered orally 
to mice retarded tumor growth and increased survival 36%. Harris 
and associates also observed in another set of experiments that the 
acute administration of delta-9-THC inhibited 3H-thymidine uptake 
into the DXA of tumor cells but not into the DXA of bone marrow, 
spleen, testes, and brain. If the acute administration of delta-9-THC 
preferentially inhibits DXA synthesis in tumor cells in humans as 
well, then the potential usefulness of marihuana as an antineoplastic 
agent will have to be evaluated. Marihuana may also have potential 
therapeutic use as an immunosuppressant in transplantation surgery 
if the findings that it depresses cell-mediated immunity in rodents (20, 
32) are substantiated in human studies. 

Studies of teratogenicity 

Early studies of marihuana indicated teratogenic activity in rats, 
rabbits, mice and hamsters (7, 8, 36, 37). Recently, Fournieret al. (6) 
have confirmed the findings in rabbits. Mantilla-Plata and Harbison 
(21) observed that the teratogenicity of delta-9-THC in mice could be 
modified by pretreatment with phenobarbital and SKF525A. Pheno- 
barbital partially antagonized THC-induced reduction of fetal body 
weight, while SKF525A either antagonized or potentiated reduction 
of fetal body weight depending on the gestational age at which it was 
administered. In addition. SK525A significantly increased the hid- 
den. -e of THC induced fetal resorptions. By contrast, the studies con- 
ducted on rats and rabbits by the National Institute of Drug Abuse 

(99) 



100 

(22) did not show deleterious effects of marihuana on either the preg- 
nant mother or the fetus. This is reinforced by the negative finding by 
Banerjee et al. (1), that delta-9-THC administered to rats produced 
no malformations among the fetuses, except for a dose related increase 
in the incidence of spongy spinal cords. Finally, there is the negative 
report by Legator et al. (17) ; a battery of tests (including the host- 
mediated assay, microsomal activation, blood and urine studies, domi- 
nant lethal and cytogenetic — micronucleus — examination) failed to 
detect any effect of delta-9-THC administered orally in the one mouse 
strain used in all of these studies. Uyeno (44) reported increasing 
complications associated with delta-9-THC administration to pregnant 
rats. Results of a later study (45) unfortunately are not interpretable 
for lack of controls. 

The conflicting reports on teratogenic effects may be due to a number 
of variables including the specific strain used, route and time of admin- 
istration and dosage. Well designed research projects utilizing animals 
are needed to determine under what circumstances marihuana acts as 
a teratogen in animals and how these findings may be applied to hu- 
mans. To date, aside from occasional case reports, no systematic human 
studies on the teratogenic effects of marihuana have been carried out. 

HUMAN" STUDIES 

Chromosome analyses 

The assessment of genetic effects in man has been exclusively based 
on cytogenetic analysis; specifically, the examination of human chro- 
mosomes. In vitro cytogenetic studies did not show an increase in the 
frequency of chromosome breaks following the addition of delta-S- 
THC (33), delta-9-THC (41) and cannabis resin (24) to lymphocyte 
cultures, but did show dose dependent mitotic inhibition. Cytogenetic 
analyses of lymphocyte cultures from chronic marihuana smokers 
have been contradictory. The majority of these studies have been 
retrospective with comparisons made between marihuana smokers and 
controls. Seven studies of this type have been published. Negative find- 
ings were reported by Martin et al. (24) on a Jamaican population 
and by Dorrance et al. (5) on light marihuana users. Gilmour et al. 
(9) also reported that light marihuana users did not show an increased 
frequency of cells with aberrations but that polydrug users, all of 
whom used marihuana heavily, did show a significant increase in 
abnormal cells. However, the use of other drugs makes it impossible to 
interpret this increase as due specifically to marihuana. Nahas et al. 
{'■\\ ) mentioned increased chromosome damage in chronic marihuana 
smokers but did not provide further information. According to 
Morishima (27), this increase was not statistically significant. 

The three positive studies of marihuana effects on chromosomes 
should be interpreted with caution. Stenchever et al. ( \2) reported u 
significant increase in the number of cells with breaks in marihuana 
users as compared to controls (3,4$ vs. 1.2Tr ). However, as stated in 
the fourth Marihuana and Health report, "the biological significance 
of the findings remained unclear because of several methodological 
and sampling questions raised by the authors themselves" (22). Ilcrlci 
and Obe (12) reported increased exchange-type aberrations (dicen- 
t rics and translocations) in chronic cannabis users. ( lose inspection of 



101 

their data shows that five of the nine aberrations they observed 
occurred in only one of the eleven subjects. Further, chromatid and 
chromosome breaks, the most commonly reported type of aberrations, 
were not included in their analysis ; when this is done, there is no longer 
any difference between users and controls. In the third study (14) — 
the only one to examine chromosomes from direct bone marrow prepa- 
rations — the authors reported a statistically significant increase in the 
frequency of breaks. Again, the increase was accounted for by two of 
the seven heavy cannabis users; the others showed no breaks. In addi- 
tion, the total number of cells examined was small, 157 cells for all of 
the seven subjects. (In drug studies, 50-100 cells per subject are cus- 
tomarily considered minimal.) Since information on the number of 
cells analyzed for each subject was not provided, it cannot be deter- 
mined whether the number was evenly distributed among all subjects. 

Retrospective studies such as those cited above, with their many 
uncontrolled variables, make definitive interpretations and conclusions 
difficult, if not impossible. To resolve the controversy, prospective 
studies are needed. 

So far, the results of only two prospective studies (with subjects 
serving as their own controls) have become available and both have 
been negative. Xichols et. al. (34) did not detect an increase in the 
percent of cells with breaks following the oral administration of 
hashish extract (containing THC. CBX and CBD) , marihuana extract 
(delta-9-THC alone) and synthetic delta-9-THC to 30 subjects follow- 
ing a variety of schedules. The second study (a 94-day study with 
72 days of unlimited smoking of marihuana cigarettes containing 
approximately 2.2% delta-9-THC) found no increase in the break 
frequency when baseline and post-exposure values were compared 
(25). However, subjects in both studies were all marihuana users and 
their baseline values may already have been elevated above those of 
non-drug using controls. Thus, even these prospective findings are not 
definitive. 

Effects on chromosome complements have also been published. 
Leuchtenberger et. al. (18. 19). using an in vitro exposure of human 
lung cells, reported a relative increase in aneuploid cells. Even more 
strikingly. Morishima (26) reported that in marihuana smokers, a 
high proportion of cells (30.6%) contained from 5-30 chromosomes 
instead of the normal 46. In a subsequent study (28) , the in vitro addi- 
tion of delta-9-THC to leukocyte cultures was found to increase the 
frequency of cells with abnormally low chromosome numbers. The 
possibility that these types of cells have been overlooked by other 
investigators as technical artifacts, or that these cells may indeed be 
technical artifacts, is not settled. Since it markedly reduces the poten- 
tial for technical artifacts, use of the flow microfluorometry technique 
to measure DXA content in intact lymphocytes from marihuana 
smokers and to compare it with DXA content of nonusers may resolve 
this question. 

At this time, there is no conclusive evidence that the consumption 
of marihuana causes chromosome damage. Indeed, the two prospective 
studies carried out as part of large biobehavioral investigations on the 
effects of marihuana did not show increased break frequencies when 
baseline and post-exposure values were compared. There are no data 
available, however, on the long-term consequences of marihuana use. 



102 

Immune responses 

The immune system of man is compartmentalized into two pan-: 
cell-mediated immunity and humoral- or antibody-mediated immunity. 
Each is dependent upon a major subpopulation of lymphocytes, the 
T- or thymus dependent cells and the B- or thymus independent colls. 
respectively. The initial publication was that of Nahas and associates 
(31) reporting that in vitro cell-mediated immunity*, as assessed by 
autogenic (phytohemagglutinin) and allogeneic cell stimulation, was 
significantly depressed in 51 chronic marihuana users compared to 81 
controls. Indeed, it was depressed to a level similar to that seen in 
patients with known T-cell immunity impairment (uremia, cancer and 
transplant patients). 

Investigations attempting to replicate this finding have led to contra- 
dictory reports. Gupta et. al. (10) compared by rosette formation fche 
circulating populations of T- and B-cells in 23 healthy chronic mari- 
huana smokers and 23 normal controls. They found that the mean per- 
centage of T-cells forming rosettes was significantly lower in the mari- 
huana smokers while the percentage of B-cell forming rosettes was 
similar in both populations. One might conclude, therefore, that smok- 
ing impaired T-cell function. Intradermal testing, however, on a limi- 
ted subsample of marihuana smokers (including those with low or 
normal percentages of rosette forming T-cells) revealed no correlation 
with the presence or absence of a positive reaction to one of more anti- 
gens tested. Therefore, the results of this study concerning T-cell func- 
tion are equivocal : When measured by rosette-formation. T-cell func- 
tion was impaired: when measured by intradermal challenge, it was 
not. Peters< n el al. (38) also reported significantly lower percentages 
of rosette-forming T-cells in marihuana smokers, while B-cells re- 
mained normal. Although the responsiveness to phytohemagglutinin 
was not significantly different from that of controls, in that same study 
the cells from smokers did tend to be less responsive suggesting pos- 
sible impairment of T-cell function. Serum levels of immunoglobulins 
(i. A and M (a measure of B-cell function) were similar in marihuana 
smokers and non-smokers. Further, the capability of polymorphonu- 
clear leukocytes to phagocytize killed veast cells was reduced in smok- 
ers (phagocytic activity of polymorphonuclear leukocytes is a neces- 
sary prerequisite for the transformation of lymphocytes into 
macrophages which process antigens in the immune system). 

The effects of marcomolecular synthesis (i.e.. I)N V. K\A and pro 
tein synthesis) in lymphocyte cultures from normal controls exposed 
in vitro to many of die natural cannabinoids have been investigated. 
(u si) man and Khurana (3) reported thai in vitro incubation of coni rod 
Lymphocytes with delta-9-THC, cannabinol, and cannabidiol for one 
hour gave a dose-related reduction in rosettes. DeSoize et al. (4) re- 
potted that in vitro addition of the natural cannabinoids (delta-9- 
THC. delta 8-THC, cannabinol, cannabidiol, cannabichromene, and 
cannabicyclol) to human lymphocyte cultures all affected DNA, RN V 
and protein synthesis as measured by uptake of -UI thymidine, 3H- 
uridine, and 3H-leucine, respectively. These two laboratories also re- 
ported positive findings on cell-mediated immunity. Results obtained 

by Blevins and Regan (2) confirmed inhibition of DNA, UNA and 
protein synthesis following the in vitro addition of delta-9-THC to 



103 

human diploid fibroblast, neuroblastoma cells and mouse neuroblas- 
toma cells in culture. Further analysis delected no effect on either DXA 
repair synthesis or uptake of radioactivity labelled precursors into the 
cell, but did demonstrate that the introcellular pool sizes of these pre- 
cursors were depressed 50%. This last, finding could account for the 
reduced synthesis reported by others. 

All of the studies discussed so far point to impairment of cell 
mediated immunity in marihuana users. There are other-, however, 
which failed to confirm such impairment. Silverstein and Lessin (40) 
in an vivo study evaluated the immunocompetence of 22 chronic mari- 
huana smokers compared to 60 controls by the gross criterion of ability 
to be sensitized to DNCB (2,4-dinitrochlorobenzene) and found no 
differences. White et al. (43) using both PHA and pokeweed mitogens 
in a vitro study, also reported no impairment of mitogen-induced 
blastogenic response in twelve chronic marihuana users as compared 
to twelve matched controls. Lau et al. (15) in a prospective study could 
detect no differences in either peak level of response to PI I A or concen- 
tration of PHA at which the maximal blastogenic response occurred. 
However, they did find that in cultures without PHA. the Level 
of 3H-thymidine incorporation was higher in marihuana smoker- than 
controls. These investigators carried out assessments before and after 
fourteen days of oral doses of 210 mg day delta-9-THC and at a one- 
week follow-up. Rachelefsky et al. (39) in a prospective study evalu- 
ated the immune system of twelve chronic marihuana smokers before 
and after 64 consecutive days of smoking unlimited quantities of mari- 
huana cigarettes containing approximately 2.2% delta-9-THC. They 
found that baseline total T-eells and B-cells were significantly lower, 
than controls but increased to normal by the 63rd day. suggest ing t hat 
factors other than marihuana smoking may have caused the depression 
seen at baseline. Response to PHA and allogeneic cells was normal and 
did not change over time; serum levels of immunoglobulins G, A and 
M were also within normal limits in their study. 

Some progress toward reconciling these contradictory findings will 
be possible when the impact of certain subtle procedural variations 
becomes known. For example. Xahas et al. (30). found that the cyto- 
toxic effect of delta-9-THC added to 72-hour lymphocyte cultures for 
the initial 24 hours could be reversed by prolonged washing of the 
cells with the nutrient medium RPMI. That is. the level of incor- 
poration of tritiated thymidine at 72 hours was the same in treated 
and non-treated cultures. They surmised that the negative findings 
by White et al. (43) may have been the result of the washing pro- 
cedure used in the isolation of lymphocytes; the cell-bound THC may 
have been washed away. Xahas et al. also found that THC induced 
inhibition of thymidine incorporation increased as the serum concen- 
tration of the culture medium decreased. This, they suggested, could 
help resolve an apparent inconsistency between two earlier findings: 
the Xahas et al. results summarized above (31), which showed marked 
inhibition of DXA synthesis in a medium with a serum concentration 
of 10%, and a later study (20) which examined the effect of THC on 
healthy blood in vitro and found the inhibition to be considerably 
less with a serum concentration of 20^. However, even this may not 
be an adequate explanation since in the first study fetal calf serum 
was used and in the second, pooled human serum. 



104 

There is general agreement among investigators that marihuana 
smokers taken off the street and tested have a reduced number of 
T-cells as measured by rosette formation. In light of the report by 
Rachelefsky et al. (39) that the initially low level of T-cells returned 
to normal while subjects were confined on a ward smoking quality 
controlled marihuana cigarettes, it may be concluded that some as yet 
unidentified variable, and not marihuana, may be the cause of the 
reduced number of T-cells seen in chronic drug users. The relation- 
ship between reduced T-cell rosette formation and immunologic func- 
tion, as assessed by mitogen and/or allogeneic cell stimulation, is not 
clear since Petersen et al. (38) reported a significantly lower mean 
percentage of T-cells in marihuana smokers than controls, but no 
statistically significant differences in PHA responsiveness. There is 
as yet no evidence that marihuana smokers are more susceptible to 
diseases known to be associated with lower percentages of T-cells 
(e.g., cancer, viral infections) and/or reduced responsivity to mito- 
gens. Also, skin testing of chronic marihuana smokers indicates intact 
and normal T-cell functions. B-cell function, too, appears to be normal 
regardless of how assessed. 

SUMMARY AND CONCLUSION 

The retrospective design and other methodological imperfections of 
most human studies, whether chromosomal or immune, leave much to 
be desired and preclude definitive conclusions. For example, informa- 
tion on nutrition, health care, recent radiation exposure and drug use 
pattern — all of which are variables known to affect both the genetic 
and immune systems — is generally obtained retrospectively from the 
participating subjects and is, therefore, of dubious validity. The po- 
tential inaccuracy of such information may doom any attempt to iden- 
tify a deleterious effect of a specific drug, like marihuana, even were 
the composition of illicitly obtained marihuana known. Many of the 
other methodological questions now plaguing researchers could be 
settled by the collaboration of several laboratories, particularly those 
reporting contradictory findings, in a single prospective double-blind 
research design with appropriate control groups. 

There is no information on the teratogenic effects in humans and it 
may take several generations to detect them. The reports on teratogenic 
effects in animals are contradictory and further rigidly designed ex- 
perimental studies are needed to supplement the few done so far. 

Bearing in mind the limitations of the studies discussed in this 
report, there is at this time no conclusive evidence that the consump- 
tion of marihuana causes chromosome damage. The studies which have 
been most carefully controlled have failed to sIioav such damage, but 
insufficient research has been conducted to allow any definitive con- 
clusions. 

A number of investigators have reported results indicating that 
marihuana may interfere with cell-mediated immunity, but until the 
inconsistencies between these findings and the negative results which 
have also been reported are resolved, and until the implications of 
particular procedural variations are more clearly understood, the 
question of whether or not THC impairs cell-mediated immunity in 



105 

humans remains a moot one. There is preliminary evidence, however, 
that in certain rodents delta-9-THC depresses cell-mediated immunity 
and preferentially inhibits DNA synthesis in tumor cells as compared 
to cells of normal tissue. It is important, therefore, to verify the anti- 
immune and anti-tumor activity of delta-9-THC in animals since, if 
these findings are confirmed and found to hold true for humans, delta- 
9-THC may have potential as an immunosuppressing and antineo- 
plastic agent. 



67-062 — 7( 



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6. Fournier, E., Rosenberg, E., Hardy, N. and Nahas, G. Teratologic effects of 
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16. Lefkowitz, S. S. and Chiang, C. V. Effects of delta-9-tetrahydrocannabinol 
on mouse spleens. "Research Communications in Chemical Pathology and Pharma- 
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17. Legator, M. S., Weber, E.. Connor, T. and Stoeckel, M. Failure to detect 
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24. Martin, P. A., Thorburn, M. J. and Bryant, S. A. In vivo and in vitro studies 
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25. Matsuyama, S. S. and Jarvik, L. F. Chromosome studies before and after 
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108 

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"Pharmacologist." 17(2) : 181 (1975). 



CHAPTER 9 

Therapeutic Aspects 

Cannabis is one of the most ancient of healing drugs. It was and is 
an important folk medicine in many cultures. This fact alone is no 
reason to expect that it will qualify in today's stringent tests of med- 
ical efficacy and pharmacologic toxicity. One should not, however, 
summarily dismiss the possibility of therapeutic usefulness simply 
because the plant is the subject of current sociopolitical controversy. 
The controversy makes its impartial evaluation more difficult, but just 
because a substance has a potential for harm does not mean that it 
may not also have potential benefits. Furthermore, unaltered mari- 
huana will not be the ideal preparation if some significant area of 
usefulness is found. Even its active cannabinoids can be improved upon 
by synthetic chemists. The benzopyran structure is a unique one which 
can be modified at many positions on the molecule. If the psychological 
changes of cannabis are not desired, they can be eliminated. If water 
solubility is preferred, it can be achieved. Although a good deal of 
further testing will be needed, there is a promise that certain of the 
pharmacologic effects of cannabis can be helpful. 

When one surveys the specific therapeutic indications, some seem 
more promising than others. It is possible that cannabinoids may have 
a contribution to make in the treatment of glaucoma and asthma. 
Despite the recent finding that in certain animals, delta-9-THC is a 
convulsant in addition to being an anticonvulsant, some of the syn- 
thetic compounds may, one day, be helpful in managing certain forms 
of epilepsy. Inasmuch as only a single preclinical study (24) has 
examined the usefulness of cannabinoids in the treatment of tumors, 
it is much too earh T to say whether cannabis might have an anti-tumor 
action in man. 

Some role may be found for a cannabinoid as a tranquilizer or a 
sedative-hypnotic. However, it will have to compete with a number 
of quite effective drugs already marketed for this purpose. Because 
of recent contradictory findings, a definite statement concerning the 
value of cannabis as an analgesic or antidepressant cannot be made 
at this time, but its antiemetic and euphoriant activity could provide 
needed relief for cancer patients undergoing chemotherapy. There is 
no evidence at present that the usefulness of cannabis exceeds that of 
currently available preanesthetic agents or those now in use for detoxi- 
fication of patients in various drug and alcohol dependency states. 

In addition to the possibility that specific benefits may some day, 
accrue, another reason for therapeutic interest in the cannabinoids is 
the possibility that their mechanisms of action may be different from 
the standard preparations. The elucidation of these mechanisms would 
be even more important than the finding of another therapeutic agent. 

(109) 



110 



THE ANCIENT LORE 



The therapeutic use of cannabis predates recorded history. The earli- 
est written reference is to be found in the fifteenth century B.C., 
Chinese Pharmacopeia, the Rh-Ya (16). From the Chinese plateau its 
use as a folk medicine, ritual potion, fabric and intoxicating agent 
spread to India, the Middle East and far beyond. 

An examination of the diverse claims made for cannabis as a medica- 
ment during past epochs reveals that many cannot be justified by the 
current knowledge of its pharmacologic activity. For instance, it had 
wide use as a lotion and poultice for a variety of skin afflictions. It had 
purported effectiveness in cases of leprosy, gonorrhea and arsenic poi- 
soning. The smoke was tried in enema form for strangulated hernia 
and an application of the juice of the leaves was recommended for 
dandruff and vermin infestation. 

On the other hand, a rationale can be found for certain of the early 
medicinal practices. Cannabis was widely used in painful conditions 
like neuralgia, dysmenorrhea and toothache aiid its relaxant and eu- 
phoriant properties may well have been utilized in the treatment of 
melancholia and hysteria. Because of its purported analgesic effect, 
supported by some recent findings, cannabis also found service in minor 
operations like circumcision and boil lancing. 

Cannabis was one of the most important drugs in the Indian Materia 
Medica at the turn of this century (54). It was, and is, widely used 
in rural areas of the Indian subcontinent for asthma and bronchitis. 
A bronchodilator action has recently been quite well established, but 
cannabis is more likely to be a cause of, rather than a cure for, bron- 
chitis. It was known to be an appetite stimulator; and this usage is 
confirmed in numerous subjective reports, although no precise mech- 
anism for assessing the appetite-enhancing effect is available. 

One interesting effect of bhang and ganja as reported by the Indian 
Hemp Drug Commission, and more recently from Jamaican (57) and 
Costa Kican studies is the assertion that it is a ''creator of energy" — 
that it increases staying power, relieves fatigue and is a stimulant. 
The Jamaican report told of its use as an energize'r and motivator to 
work. Ganja breaks in back country Jamaica seem to be the equivalent 
of the North American coffee breaks. Employers have been known to 
supply their workers with ganja to "get more work out of them." This 
reason for use among laborers and fanners stands in sharp contrast 
with our concerns about a marihuana-induced "amotivat ional 
syndrome." 

The scattered but persisting reports about an aphrodisiac property 
are not easy to evaluate. Much seems to depend upon the mental set of 
tlie consumer. If it is taken for that purpose, sexual interest, activity 
and enjoyment are likely to be enhanced. On the other hand sexually 
abstinent Indian monks used cannabis to diminish sexual drives ind 
as an aid to meditation. While it may enhance sensory perception, 
prolong the subjective experience of time and reduce inhibitions, and 
thus intensify sexual experience, cannabis appears to have no direct 
effect upon sexual drive states (7). In fact, in view of the reports of 
lowered plasma testosterone levels after heavy usage, potency may, m 
some instances, be reduced (35). 



Ill 

Many therapeutic references can be found regarding the seeds of 
Cannabis saliva (23). For example, the seventh century Scythians in- 
haled and bathed in the vapors of hemp seeds thrown onto a fire, and 
"they howled with joy." The seeds contain essentially no active tetra- 
hydrocannabinols, so that whatever joy there was must have been due 
to the effects of the sauna. A persistent theme that runs from ancient 
times up to the present is the healing effect of external applications 
of cannabis. The potential efficacy of cannabis as a topical antibiotic 
has been most extensively researched in Czechoslovakia (30). 

THE MIDDLE PERIOD 

During the latter half of the nineteenth century a resurgent interest 
in the medical usefulness of the hemp plant developed. Well ov 
hundred papers appeared in the medical journals of the day. Some of 
these reports are worth citing, however briefly. In Calcutta. O'Shaug- 
nessey (47) tried cannabis on patients with a variety of ailments, in- 
cluding tetanus, rabies, epilepsy and rheumatism. He reported favor- 
ably on its anticonvulsant, analgesic and muscle-relaxing properties. 
This sparked a flurry of clinical investigations including those of 
M'Meens (42) who considered it a sedative-hypnotic, useful in such 
diverse disorders as neuralgia, dysmenorrhea, asthma and sciatica. 
Many favorable reports appeared, including those of Birch (3) and of 
Mattison (37) who recommended cannabis enthusiastically for the 
treatment of morphine, alcohol and other addictions. In 1890 Reynolds 
( 55) wrote of its value in senile insomnia and tic douloureux (trigemi- 
nal neuralgia). 

During this period Moreau de Tours (43) successfully treated obses- 
sive compulsives, melancholies and patients with many other chronic 
psychiatric syndromes. His positive findings were confirmed by some, 
but not by other studies. 

Despite the encouraging testimonials about cannabis, the drug began 
to fall into disuse at the beginning of the twentieth century. In retro- 
spect, it would appear that the following reasons combined to account 
for its neglect : 

(1) Different batches of the plant had widely varying potencies, 
with some essentially ineffective and others stronger than the prescriber 
expected ; 

(2) The drug had a poor shelf life. Many of the extracts of canna- 
bis were practically inert by the time they were dispensed. Delta -9- 
tetrahydrocannabinol gradually breaks down into cannabinol at room 
temperature or when exposed to daylight and air. Cannabis sativa was, 
therefore, unreliable, and some of the contradictory clinical opinions 
might be explained on this basis. 

(3) Delta-9-THC is extremely insoluble in water and crosses the 
gastrointestinal wall with difficulty. It is for this reason that the oral 
route is two or three times less effective by weight than the pulmonary. 

(4) Synthetic, water soluble analgesics and hypnotics which had a 
much more predictable, stable pharmacological action were beginning 
to appear. 

(5) The final blow was the Marihuana Tax Act of 1937 which clas- 
sified the drug as a narcotic. By that year, however, it was hardly 
employed in medical practice in the United States. 

Dc !U: ' " -■-! 

U.P.F. 






112 

Even when the first synthetic tetrahydrocannabinol, pyrahexvl 
(Synhexyl), became available for clinical trials, it was not widely 
employed. Some work was done by Thompson and Parker (67), who 
treated various drug withdrawal syndromes with some success. In what 
may have been the first double blind study with a cannabinoid, Parker 
and Wrigley (48) administered it to 57 depressed patients. They were 
unable to demonstrate a significant difference between pyrahexyl and 
the placebo. This study has been criticized by Grinspoon (23) for hav- 
ing used an inadequate dosage level. At any rate, both favorable and 
unfavorable reports with pyrahexyl can be found in the literature. It 
was tried in depressions, epilepsy and in addictive states. The value of 
many of the earlier reports is indeterminate. They were uncontrolled, 
poorly designed and impressionistic. Still, they did provide certain 
clues which have been exploited in present day pharmacologic 
investigations. 

THE CURRENT PERIOD 

The systematic study of the clinical pharmacology of cannabis is 
less than ten years old. It required a number of scientific advances and 
administrative decisions before it could begin. These included : 

(1) The total synthesis of delta-9-THC by Mechoulam (38) per- 
mitting the manufacture of sufficient material for investigators. 

(2) The clarification of the relationship between delta-9-THC and 
the plant material (39) . 

(3) The development of a source of uniform, assayed marihuana b}^ 
the University of Mississippi group (52) under a NIDA contract, 

(4) The availability of a reliable assay procedure for delta-9-THC 
in marihuana. 

(5) The funding of animal and human studies designed to clarify 
the physiologic, pharmacologic and psychologic effects of cannabis. 

(6) The availability of various cannabinoids for research purposes 
from the National Institute on Drug Abuse. 

(7) The recent development of assay methods which can qualita- 
tively identify cannabinoids in biological fluids (1). 

Cannabis has been found to have some therapeutic potential in a 
number of diverse areas. They can be divided into two general groups, 
those that utilize the psychologic changes that the drug induces and 
those that do not. In the latter instance, the subjective symptoms often 
become undesired side effects of the drug. 

The non-psychologic research directions includes intraocular pres- 
sure reduction, bronchodilator, anticonvulsant and tumor growth re- 
tardation. 

The therapeutic efforts which rely on changes in the psychic state 
are : sedative-hypnotic, analgesic, antidepressant and tranquilizer, pre- 
anesthetic, antinauseant and antiemetic, and drug and alcohol depend- 
ence therapy. 

Intraocular pressure {I OP) reduction 

Hepler and associates (25, 2G) undertook a study of the various 
ocular alterations produced by smoking cannabis in 1970. Among their 
early findings were a consistent, dose-related, clinically significant fall 
in IOP in subjects with normal ocular tension. The IOP was also re- 



113 

duced with oral delta-9-THC and, to a lesser degree, with cannabinol 
and cannabidiol. Seven of eleven patients with ocular hypertension 
demonstrated a drop in IOP averaging 30% which lasted four to five 
hours. Topically instilled delta-9-THC in sesame oil produced a 40% 
reduction in IOP when compared to a treatment of sesame oil eye drops 
administered to a group of twelve rabbits. 

Green et al. (20, 21) demonstrated a fall in the IOP of rabbits 
given intravenous delta-9-THC. They postulated that delta-9-THC 
interacted with the adrenergic innervation system of the eye, namely 
that alpha-adrenergic blocking agents partly inhibited the THC effect. 
Apparently, beta-adrenergic blockade also dampens the delta-9-THC 
effect. The result of these adrenergic activities is a dilation of the 
efferent blood vessels. These effects were found to be modulated via an 
inhibition of prostaglandin synthetase. 

Cooler and Gregg (12) compared intravenous (i.v.) doses of 1.5 
and 3 mg of delta-9-THC, 10 mg diazepam (Valium) and a placebo 
in ten volunteers. IOP was diminished 29% with the low and 37% 
with the high deita-9-THC dosages. Diazepam lowered the pressures 
10% and placebo 2%. These investigators also measured analgesia 
and noted no cutaneous or periosteal analgesic effects. Their subjects 
manifested an increased anxiety level on both doses of delta-9-THC. 
This study and others indicate that the IOP reduction is not due to 
any relaxing or euphoriant effects of cannabis as suggested by Flom 
et al. (18). 

Bronchodilation 

During 1973 two articles referring to a bronchodilator effect 
appeared. Vachon et al. (68) studied the effects of a single adminis- 
tration of smoked marihuana on normal subjects and asthmatic 
patients. Airway resistance decreased significantly permitting an in- 
crease in specific airway conductance and mean expiratory flow rates. 
The bronchoconstriction of the asthmatic patients was reversed for 
hours. 

Tashkin et al. (64) did a double blind study of 32 non-naive, male 
subjects randomly assigned to a placebo group, a 1% delta-9-THC 
and a 2% delta-9-THC group. The investigators found that both 
dosages decreased airway resistance with a peak at fifteen minutes and 
with activity still present after an hour. Subsequently, they examined 
dose response curves with a placebo and 10, 15 and 20 mg of oral 
delta-9-THC and found that peak effects for the THC dosages were 
obtained at three hours. Persistent effects were evident for six hours. 

Tashkin and associates also induced bronchospasm in asthmatics 
with methacholine or exercise (65). In a single blind fashion 10 mg of 
smoked delta-9-THC was compared to 1.25 mg of inhaled isoproterenol 
(Isuprel), both placebo controlled. Bronchospasm was relieved 
promptly by both drugs, not by their placebos. The isoproterenol had 
a higher peak effect, but the marihuana had a longer lasting activity. 

The irritant quality of smoked cannabis, with its terpenes and coal 
tars, makes it poor delivery vehicle for asthmatics. At present, an aero- 
solized delta-9-THC is being tried (46). The results of a pilot study 
are encouraging, showing that the aerosol produced a mean peak in- 
crease above baseline of 89% — much greater than the increase observed 
when the same amount (10 mg) of delta-9-THC was smoked. Also, 



114 

systemic effects such as the tachycardia and the "high" were not as 
pronounced with the aerosolized preparation. 

This group also attempted to clarify the mechanism of broncho- 
dilator action (59). In one set of experiments, six young males either 
smoked a cigarette containing 10 mg delta-9-THC or were injected 
with atropine before being challenged Avith methacholine. In contrast 
to atropine the cannabis-induced increase in specific airway conduct- 
ance was not blocked by a methacholine challenge. In succeeding sets 
of experiments, the effects of combinations of propanolol and mari- 
huana and isoproterenol and marihuana on young males were ex- 
amined. Unlike isoproterenol, propanolol did not block the cannabis- 
induced increase in specific airway conductance. Apparently, cannabis 
is a bronchodilator independent of beta-adrenergic or antimuscarinic 
effects. 

A nticonvu Isan t 

Much of the work investigating the anticonvulsant properties of 
cannabis has been preclinical. The effects of cannabinoids on animal 
seizures resembling epileptic attacks, whether induced b} T pentylen- 
tetrazol (Metrazol )or by audiogenic or electrical means, have been 
recently examined. Consroe et. al. (8, 9, 10) found that delta-8- and 
delta-9-THC blocked all three types of seizures in a dose-related man- 
tier, and that these cannabinoids were qualitively comparable to di- 
phenylhydantoin (Dilantin). Boggan (4) confirmed the effect of delta- 
9-THC in audiogenic seizure susceptible mice. 

Rat hippocampal seizures precipitated by afferent electrical stimula- 
tion were used in another study of anticonvulsant activity (IT). Can- 
nabinoids were effective — more effective than diphenylhydantoin — in 
diminishing these seizure discharges. Cannabidiol was most potent, 
followed by cannabiuol, delta-9-THC and delta-8-THC in order of 
effectiveness. Interestingly, the psychologically non-active cannabi- 
noids outperformed the active ones. 

Karler et al. (31, 32, 33) showed that tolerance developed to the anti- 
seizure activity in the maximal electroshock test in rats treated with 
delta-9-THC and in mice treated with delta-9-THC, cannabidiol, di- 
phenylhydantoin and phenobarbital. In other electrical seizure models 
tolerance was variable and specific for each model. It is possible that 
cannabidiol, which has no psychotoxicity or cardiotoxicy, has the fur- 
ther advantage of being a better anticonvulsant than delta-8-TIIC. 
Mechoulam (40) reported that 6-oxo-eannabidiol diacetate is a promis- 
ing anticonvulsant. 

The Davis and Ramsey pilot study in 1949 (13) examined the effect 
of tetrahydrocannabinols on five epileptic hospitalized children who 
had been receiving diphenylhydantoin or mephenytoin (Mesantoin) as 
medication. Two eases showed improvement after receiving one can- 
nabinoid, while transfer to a second cannabinoid produced mixed re- 
sults. Very little human investigation of the anti-epileptic properties 
of the cannabinoids has been done since. 

Convulsanl as well as anticonvulsant action has been demonstrated 
for cannabis. This i^ usually mani Test when toxic or high chronic doses 
are used. However, Consroe et al. (11) have bred a strain of New- 
Zealand rabbit which is quite susceptible to delta-9-TIIC seizures. 
Doses of 0.1-0.8 mg/kg i.v. produced behavioral seizures regularly. 



115 

Spontaneously epileptic beagles were given delta-9-THC, cannabidiol 
or a placebo for twenty consecutive days. Myoclonic jerks and gen- 
eralized seizures were observed only in those dogs receiving 3-5 mg/kg 
orally. A single case report suggests that cannabidiol may activate 
spiking in epileptic patients (69) . 

In view of the problems involved with delta-9-THC (insolubility, 
variable oral absorption, psychotoxicity, tachycardia, convulsant po- 
tential), three new benzopyrans have been synthesized (51). These are 
dimetlrylheptylpyran (DMHP) analogues which are more active than 
diphenylhydantoin in rats given the supramaximal elect roshock test. 
These new compounds have varied anticonvulsant profiles, do not pro- 
duce tolerance and have minimal toxicity. 

Retardation of tumor growth 

Harris et al. (24) have reported that mice inoculated with Lewis 
lung adenocarcinoma materials showed reductions of tumor size from 
25 to 82%, depending upon the dose and duration of treatment, with 
subsequent administrations of oral delta-9-THC. delta-8-THC and 
cannabinol, but these investigators did not find such an effect with 
cannabidiol. Cannabinoids increased survival time by a quarter to a 
third compared to an increase of about 50% for cyclophosphamide. 
Friend leukemia virus growth was also inhibited by delta-9-THC, but 
L1210 murine leukemia was not. In vitro experiments confirmed the 
animal inhibition of growth, leading the authors to conclude that cer- 
tain cannabinoids possess antineoplastic properties by virtue of their 
interference with RXA and DXA synthesis. 

The therapeutic studies which rely upon the psychologic effects of 
marihuana follow. 

Sedative hypnotic 

Freemon et al. (19) confirmed the observation of others that delta- 
9-THC, like most hypnotics, reduces REM time during sleep. How- 
ever, in contrast to findings with other hypnotics like the barbiturates, 
the abrupt withdrawal of THC after six consecutive nights of usage 
failed to produce a REM rebound, although mild insomnia was ob- 
served. Sofia and others (61) have demonstrated that pretreatment of 
laboratory animals with delta-9-THC reduces the dose of barbiturates 
needed for hypnosis and increases sleep time. 

Studies attempting to exploit the well-known relaxing, sedating 
properties of cannabis have been performed. Two studies conducted by 
Meu and his colleagues (44) exploring the use of delta-9-THC as a 
bedtime sedative are difficult to reconcile with one another. In the first 
study nine subjects with sleep difficulties were given 10, 20 or 30 mg of 
delta-9-THC or a placebo at weekly intervals, double blind. The drug, 
as compared to the placebo, significantly reduced the time needed to 
reach a state of sleep. Furthermore, sleep was less interrupted during 
the drug nights. Side effects were mild, but they grew in number with 
increasing dosage. The main complaint was of feeling hungover or 
'•stoned" the next day. 

In the second study the delta-9-THC doses were reduced to 5, 10 and 
15 mg to reduce hangover. These were compared to a placebo and to 
500 mg of chloral hydrate, a well-established hypnotic. Surprisingly, 
neither the chloral nor the delta-9-THC facilitated sleep induction or 



116 

extended the duration of sleep as compared to the placebo. At the 15 
mg dose level, some complaints of hangover were recorded. The au- 
thors suggested that difficulties in controlling the room temperature 
during the winter may have interfered with sleep sufficiently to negate 
any possible hypnotic effects of the active substances. 

Tassinari et al. (66) reported increases in total sleep time in eight 
volunteers. Stage II sleep was increased and REM sleep was reduced. 
The doses used were rather large (0.7 to 1 mg/kg of delta-9-THC). 

Analgesic and pre-anesthetic 

One of the earliest folk uses for cannabis was its pain-relieving 
quality. A series of preclinical investigations by Ka7/makalan et al. 
(34) tended to confirm the analgesic effect. After having received 
intravenous administration of 1 mg/kg delta-9-THC, dogs received 
electric stimulation through an implanted dental electrode. The can- 
nabinoid produced a definite analgesic effect, as shown by a fourfold 
increase in pain thresholds. Tolerance to analgesia, sedation and ataxia 
occurred in eight days. In another study delta-9-THC produced pain 
reduction in mice and rats as measured by the tail flict and writhing 
tests, and in rabbits receiving sciatic nerve stimulation. The analgesia 
produced with the doses used was equivalent to morphine analgesia — 
in fact, in rats a cross tolerance between delta-9-THC and morphine 
was found. An earlier study (49) measured the effect of delta-9-THC 
on rats with electrodes implanted in aversive brain sites. A non-dose 
related elevation of the pain threshold and an attenuation of the escape 
response were recorded. 

A double blind Canadian study by Milstein (41) revealed a signifi- 
cant increase in pain tolerance among those who had smoked mari- 
huana. Using a pressure algometer, the experimenter found that ex- 
perienced subjects obtained greater analgesia than non-experienced 
subjects, although the increased pain tolerance was found only in the 
preferred hand. No effects on sensitivity to pain sensation were noted. 

In another human study Hill et al. (27) recorded opposite results. 
Here, 26 subjects received blind either marihuana smoke containing 
12 mg of delta-9-THC from a spirometer or a marihuana placebo, then 
were given electrical skin stimulation. The THC was found to decrease 
tolerance and heighten sensitivity to pain. 

In an impressionistic report Dunn and Davis (15) questioned ten 
paraplegics hospitalized in a V.A. Hospital, all of whom had admitted 
usin£ marihuana in the past. Four reported that it produced a decrease 
in phantom pain sensations, five mentioned a decrease in spasticity, and 
five noted a decrease in headache pain and an increase in pleasant 
sensations. 

Cancer patients in pain were studied by Noyes et al. (45). Patients 
were given either delta-9-THC in 5, 10, 15 or 20 mg doses or a placebo. 
Pain reduction was greater at all delta-9-THC levels than in the 
placebo condition and significantly so at the 15 and 20 mg THC levels. 
These researchers felt that the pain relief was not due to the sedative 
or euphoriant effects. 
A ntidepressat \ f 

Since marihuana tends to elevate mood, it follows that an evaluation 
of its antidepressant potential would be sought . T\o< in et al. (36) ad- 
ministered 0..°, mg/kg of (loha-9-TITC or a matching plncebo twice 



117 

daily to eight patients who required hospitalization for their affective 
disorder. The patients were all considered moderately or severely de- 
pressed. Treatment lasted a week, with placebos substituted for the 
active drug thereafter. No evidence of a significant affectual change 
could be demonstrated. In chronic depressive states a longer duration 
of drug administration is sometimes needed. 

A group at the Medical College of Virginia (53) performed a double 
blind study with cancer patients receiving chemotherapy. An initial 
starting dose of 0.1 mg/kg t.i.d. was used which was raised if previous 
doses were well tolerated. On a battery of personality tests and mood 
scales the delta-9-THC acted as a mood elevator and tranquilizer pro- 
ducing significant improvement on two or three Zung depression scales. 
Cognitive functioning was unimpaired and appetite enhancement and 
retardation of weight loss were noted from the clinical records. The 
need for narcotics was decreased, and patients had the impression that 
some pain relief resulted. Relief of nausea and vomiting was prob- 
lematic. 

Pre-anesthetic 

A number of studies have examined the role that delta-9-THC can 
play as a preanesthetic agent, with mixed results. When it was given 
prior to inhalation anesthesia, the requirement for cyclopropane and 
halothane was decreased (50, 62). Smith (60) found that normal vol- 
unteers given 200 meg/ THC intravenously experienced marked seda- 
tion with minimal respiratory depression. Also, salivation was di- 
minished, bronchodilation occurred, and cardiac output increased on 
the basis of the expected tachycardia. Although the author cautioned 
that some of Hie observed effects may have been due to the alcohol in 
which the delta-9-THC was dissolved, that amount of the drug given 
intravenously could easily have provided the manifestations recorded. 
Whether delta-9-THC has a potential usefulness in anesthesiology will 
depend on findings from additional studies. 

Gregg and Small (22) found two dosage levels of intravenous clelta- 
9-THC ineffective in controlling anxiety in oral surgery patients. In 
fact, in low doses it elevated anxiety, sometimes to a marked degree. 
Intravenous diazepam (Valium) outperformed the drug under inves- 
tigation. 

Smith (60), having searched for suitable pre-anesthetic combina- 
tions, reported that 5 mg of delta-9-THC intravenously produced fear 
in a number of patients. In combination with an opioid it provided 
useful sedation but with a marked decrease in carbon dioxide sensi- 
tivity. 'When combined with a barbiturate, the CNS depression was 
unpleasant and associated with some restlessness, but the response to 
carbon dioxide was unchanged. With diazepam definite drowsiness and 
other depressive effects were notable, and the ventilatory response to 
carbon dioxide was decreased. The investigator suggested that the 
combination of marihuana with pre-anesthetic or anesthetic medica- 
tions could lead to undesirable potentiation. 

Johnstone et. al. (29) also examined delta-9-THC in combination 
with other drugs. THC was administered intravenously after subjects 
had been pretreated with oxymorphone (OXM) or pentobarbital 
(PBL). The sedative effects of OXM were increased by THC, but the 
cannabinoid also increased respiratory depression. The combination 



118 

of PBL and THC did not cause respiratory depression but produced 
such intense anxiety and psychotomimetic reactions that four of the 
seven subjects receiving this combination were not given the full course 
of five THC doses. The investigators concluded that neither combina- 
tion was a desirable anesthetic premedication and also expressed res- 
ervations about the value of THC alone for such a purpose. 

Antinauseant and antiemetic 

Sallan (58) gave two oral courses of delta-9-THC or a placebo to a 
small number of cancer patients in chemotherapy who were not 
responding well to the conventional antiemetics. Nausea and vomiting 
were brought under control with the drug significantly more often 
than with the placebo. Sedation, which could be considered desirable 
in this group of patients, was a frequent side effect. 

Alcoholism and dimg abuse 

Rosenberg (56) has studied the response of a group of alcoholics 
and normal volunteers to marihuana cigarettes (0.4 gm/501b body 
weight) and to alcohol (2 ml vodka/kg). This investigator found that 
alcoholics tended to be less responsive to stress (mental arithmetic and 
talking to a videocamera) and were more likely to withdraw from a 
stress situation than the normals. Alcoholics became more angry and 
depressed after alcohol ingestion as measured by mood scales. Mari- 
huana produced a more positive mood state and did not interfere with 
the arousal reaction, although it greatly increased heart rate and pro- 
duced an acute paranoid or confusional state in 3 of the 27 subjects. 
This investigator also found that disulfiram (Antabuse) and mari- 
huana could be given safely together in the treatment of alcoholism. 
The study is continuing, but the early findings indicate that marihuana 
may be a suitable therapeutic adjunct for some alcoholics. 

Hine and colleagues (28) have implanted morphine pellets in rats. 
T)elta-9-THC in 1, 2, 5 and 10 mg/kg doses was injected 71 hours later. 
After one additional hour, 4 mg/kg of naloxone (Narcan) was de- 
livered. The two higher doses blocked the appearance of wet shakes, 
escapes, diarrhea and increased defecations, although neither delta-9- 
THC nor cannabidiol precipitated abstinence in these rats. The results 
indicate that delta-9-THC may be worth studying in narcotic detoxi- 
fication situations. 

Mechanism of action 

The precise mechanism by which cannabis exerts its various pharma- 
cologic, effects is not known. Burstein (5, 6) found that delta-9-THC 
reduced prostaglandin formation by inhibiting prostaglandin synthe- 
tase. Other cannabinoids also have this effect, as does blivetol, from 
which delta-9-TJIC is synthesized. Many prostaglandins exist, and it 
will be necessary to determine what effect the cannabinoids have on the 
various fractions. Prostaglandin inhibition would explain a number 
of the physiologic actions attributed to cannabis such as the intra- 
ocular pressure reducing and bronchodilating effects. 

The influence of cannabinoids on neurotransmitters has been ex- 
amined, but the results are inconsistent, Banerjee et al. (2) have shown 
that the psychologically active cannabinoids and cannabidiol are po- 
tent inhibitors of norepinephrine, dopamine, serotonin and GABA in 



119 

vitro, while the cannabinoid-biogenic amines relationship is undoubt- 
edly much more complex. Drew and Miller (14) believe that choliner- 
gic dominance best explains the mental effects. Monoamine oxidase 
inhibition of the various cannabinoids is also beginning to be studied. 

SUMMARY 

The further study of the cannabinoids for various therapeutic ap- 
plications seems worthwhile. Numerous synthetic cannabinoids have 
begun to appear; these do not have the disadvantages (insolubility, 
undesired psychic effects, instability) intrinsic in the naturally-occur- 
ring ones. Therapeutic efficacy may also be enhanced by molecular 
manipulations. Thus, it is likely that if any cannabinoid achieves clini- 
cal acceptance, it will be a synthetic. 

Findings of importance are: 1) the wide safety margin between 
effective and lethal doses, of cannabinoids; and 2) that m many in- 
stances the mechanism of action appears to differ from the medication 
commonly employed. The hemp plant and its derivative chemicals turn 
out to be neither the best nor the worst of substances. Like everything 
else it should be used for its beneficial effects and avoided for its 
noxious aspects. 



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2. Banerjee, S. P., Snyder, S. H. and Meehoulam, R. Cannabinoids : Influence 
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19. Froemon, F. R. The effect of delta-9-tetrahydrocannabinol on sleep. "Psy- 
chopharmacologia," 35:39-44 (1974). 

20. Green, K. and Kim, K. Interaction of adrenergic blocking agents with 
prostaglandin E2 and tetrahydrocannabinol in the eye. "Experimental Eye 
B • search," 15:499-507 (1973). 

21. Green, K. Marihuana and the eye. "Investigative Ophthalmology," 14: 261- 
263 (1975). 

22. Gregg, J. M. and Small, E. W. The control of anxiety in oral surgery 
patients with delta-9-THC and diazepam. "NIH Record," 26: 8 (1974). 

(120) 



121 

23. Grinspoon, L. "Marihuana Reconsidered." Cambridge : Harvard University 
Press, 1971. 

24. Hairris, L. S., Munson, A. E. and Carehman, R. A. Anti-tumor properties of 
cannabinoids. "Pharmacology of Marihuana." Edited by Braude, M. and Szara, 
S., New York : Raven Press (in press) . 

25. Hepler, R. S. and Frank, I. R. Marihuana smoking and intraocular pressure. 
"Journal of the American Medical Association," 217 : 1392 (1971) . 

26. Hepler, R. S., Frank, I. M. and Pefcrus, R. Ocular effects of marihuana 
smoking. "Pharmacology of Marihuana." Edited by Braude, M. and Szara, S. 
New York : Raven Press (in press) . 

27. Hill, S. Y., Schwin, R., Goodwin, D. W. and Powell, B. J. Marihuana and 
pain. "Journal of Pharmacology and Experimental Therapeutics," 188 : 415-418 
(1974). 

28. Hine, B.. Friedman, E., Torrelio, M. and Gershon, S. Morphine-dependent 
rats : Blockade of precipitated abstinence by tetrahydrocannabinol. "Science, 
187:44&-446 (1975). 

29. Johnstone, R. E., Lief, P. L., Kulp, R. A. and Smith, T. C. Combination of 
delta-9-tetrahydrocannabinol with oxymorphone or pentobarbital : Effects of on 
ventilatory control and cardiovascular dynamics. "Anesthesiology," 42 : 674-684 
(1975). 

30. Kabelik, J. Hanf (Cannabis Sativa) — Antibiotishes heilmittel. "Pharmazie," 
12(7) : 439-443 (1957). 

31. Karler, R., Cely, W. and Turkanis, S. A. The anticonvulsant activity of can- 
nabidiol and cannabinol. "Life Sciences," 13 : 1527-1531 (1973). 

32. Karler, R., Cely, W. and Turkanis, S. A. Anticonvulsant properties of delta- 
9-tetrahydrocannabinol and other cannabinoids. "Life Sciences," 15 : 931-947 
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33. Karler, R., Cely, W. and Turkanis, S. A. A study of the development of 
tolerance to an anticonvulsant effect of delta-9-tetrahydrocannabinol and can 
nabidiol. "Research Communications in Chemical Pathology and Pharmacology,' 
9:23-39 (1974). 

34. Kaymakcalan, S., Turker, R. K. and Turker, M. N. Analgesic effect of delta 
9-tetrahydrocannabincl and development of tolerance to this effect in the dog 
"Psychopharmacologia," 35 : 123-128 (1974). 

35. Kolodny, R. C, Lessin, P., Toro, G., Masters, W. H. and Cohen, S. Depres 
sion of plasma testosterone with acute marihuana administration. Persona 
communication. 

36. Kotin, J., Post, R. M. and Goodwin, F. K. Delta-9-tetrahydrocannabinol in 
depressed patients. "Archives of General Psychiatry," 28:345-348 (1973). 

37. Mattison, J. B. Cannabis Indica as an anodyne and hypnotic. "St Louis 
Medical and Surgical Journal," 61 : 265-271 (1891). 

38. Mechoulam, R. and Gaoni, Y. A total synthesis of d,l-delta-l-tetrahydro- 
cannabinol, the active constituent in hashish. "Journal of the American Chemical 
Society." 87 : 3273-3275 (1965). 

39. Mechoulam, R., Shani, A., Edery, H. and Grunfeld, Y. Chemical basis of 
hashish activity. "Science," 169 : 611-612 (1970) . 

40. Mechoulam, R., Lander, N., Dikstein, S., Carlini, A. E. and Blumenthal, M. 
On the therapeutic possibilities of some cannabinoids. Personal communication. 

41. Milstein, S. Pain tolerance and cannabis. Reported at the Collegium Inter- 
nationale Neuropsychopharmicologicum Convention, Paris, 1975. 

42. M'Meens, R. R. Report on the Committee on Cannabis Indica. "Transac- 
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75-100 (1860). 

43. Moreau de Tours, J. J. Psychotic depression with stupor tendency to de- 
mentia : Treatment with an extract of Cannabis indica. "Lancette Hospital 
Gazette," 30:391 (1857). 

44. Neu, C. and DiMascio, A. Hypnotic properties of THC : Experimental com- 
parison of THC with chloral hydrate and placebo. Personal communication. 

45. Noyes, R., Brunk, F., Baram, D. A. and Canter, A. Analgesic effect of delta- 
9-tetrahydrocannabinol. "The Journal of Clinical Pharmacology," 15 : 139-143 
(1975). 

46. Olson, J. L., Lodge, J. W., Shapiro, B. J. and Tashkin, D. P. An inhalation 
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47. O'Shaughnessy, W. B. On the preparation of the Indian hemp or Gunjah 
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67-062—76 9 



122 

48. Parker, C. S. and Wriglej, F. Synthetic cannabis preparations in psychiatry : 
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49. Parker, J. M. and Dubas, T. C. Automatic determination of the pain thresh- 
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Clinical Pharmacology, Therapy and Toxicology/' 7(1) : 75-81 (1973). 

50. Paton, W. D. M. and Temple, D. M. Effects of chronic and acute cannabis 
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51. Plotnikoff. X. P., Zaugg, II. E., Petersen, A. C, Arendsen, D. L. and Ander- 
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52. Quimby, M. W., Doorenbos, N. J., Turner. C. E. and Masoud, A. Mississippi 
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53. Regelson, W. and Butler, J. R. Treatment effects of delta-9-THC in an ad- 
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55. Reynolds, J. R. Therapeutic uses and toxic effects of Cannabis iudica. 
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56. Rosenberg, C. M. The use of marihuana in the treatment of alcoholism. 
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57. Rubin, V. and Comitas. L. "Ganja in Jamaica." The Hague : Mouton, 1975. 

58. Sallan, S. E., Zinberg, N. E. and Frei, D. Antiemetic effect of delta-9-tetra- 
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59. Shapiro, B. J. and Tashkin, D. P. Effects of beta adrenergic blockade and 
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60. Smith, T. C. Combination of delta-9-tetrahydrocannabinol with diazepam. 
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61. Sofia, R. D. and Knobloch, L. C. The interaction of delta-9-tetrahydroean- 
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62. Stoelting. R. K., Martz, R. C, Gartner, J., Creasser, C, Brown. D. J. and 
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63. Tashkin, D. P., Shapiro, B. J. and Frank. I. M. Acute effects of smoked 
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64. Tashkin, D. P., Shapiro, B. J. and Frank, I. M. Acute pulmonary physio- 
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65. Tashkin, D. P.. Shapiro, B. J., Lee, Y. E. and Harper, C. E. Effects of smoked 
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(1974). 



AUTHOR INDEX 



Abbott, S. R., 29, 32 

Abel, E. L., 53, 54, 56, 57, 63, 66, 69, 72 

Abelson, H., 3, 17, 18, 25 

Ablon, S. L., 85, 91 

Abraham, D. J., 28, 33 

Abramson, H. A., 8, 78, 93 

Abu-Shumways, A., 29. 32 

Adams, A. J., 81. 93, 113, 120 

Adams, P. M., 39, 46. 62, 63. 66, 69, 72 

Agarwal. S. S., 61, 68, 69, 74 

Agurell, S., 29, 30, 33, 34, 77, 98, 112, 

120 
Akins, F., 45, 46, 52, 57 
Aliapoulios, M. A., 38, 47, 79, 93 
Allen, M., 100, 108 
Altman, H., 11, 86, 91 
Alues, C. N., 54, 56, 57 
Ambrosetto, G., 7, 80. 97. 116, 122 
Amit, F., 15, 62, 66, 71, 72 
Anderson, J. E., 61. 68 
Anderson, M., 39. 47, 91 
Anderson, P. F., 39, 44, 46, 52, 57, 69. 70, 

72, 115, 122 
Andhuber, G., 38, 47 
Angelico, L., 8, 77, 91 
Archer, R., 75, 77, 95 
Arendsen, D. L.. 40, 49, 115. 122 
Armand, J. P.. 81, 97. 100, 102. 103, 107 
Arngfield, N., 115, 122 
Aronow, W. S.. 8, 42. 46. 77, 91, 96 
Arora, R. B., 61. 68, 69, 74 
Arora, S., 41, 46 
Asberg, M., 29, 34, 112. 120 
Askew, W. E., 43, 46 
Atkinson, R. B., 3, 17, 18, 25 
Atkinson, R. C, 82, 92 
Avery, D. H., 62, 68, 82, 85, 96 

Babor, T. F., 79, 95 

Backhouse, C. I., 78, 91 

Bader-Bartfai, A., 75, 95, 96 

Bakker, C. B., 84, 91 

Banerjee, S. P.. 43, 46, 118, 120 

Bannerjee, B. C, 100, 106 

Baram, D. A., 62, 68, 82, 96, 116, 121 

Barnes. C. 69, 72 

Barratt. E. S., 39, 46, 62, 63, 66, 69, 72 

Barry, H., 53, 54, 55, 59, 64, 65, 66, 67, 70, 

74 
Baugh. E. L., 52, 58, 64, 66 
Beahrs, J. O., 82, 91 
Bech, P., 75, 91 
Beck, E. C, 69, 74 
Bellville, J. W.. 79. 98 
Ben-David, M., 39, 48 



Benowitz. X. L., 77, 88, 89, 90. 91, 94, 

103, 106 
Ben-Zvi. Z., 30, 32 
Bercht. C. A. L., 28, 32, 33 
Bergen, J ,R., 30, 32 
Berger, H. S., 52, 58 
Bickel, P., 82, 92 
Bieniek, D., 29, 33 
Biggs. D. A.. 83. 96 
Billets, S., 29, 34 
Binder, M., 30, 33, 75,95 
Birch. E. A., Ill, 120 
Blackford. L.. 4, 20, 25 
Blaine, J. D.. 9, 83, 95 
Blevins, R. D., 102. 106 
Bloom, A. D., 100, 106 
Bloom, R., 21, 25 
Blumenthal, M., 114, 121 
Board, R. D., 76, 94 
Boggan, W. O., 114, 120 
Boiotow, I., 62, 66 
Borg, J., 82, 88, 91 
Borgen, L. A.. 44, 46, 47, 51, 53, 57, 63, 

66, 99, 107 
Boulougouris. J.. 86, 88, 90, 97 
Bourke, D., 77, 78, 95 
Bowins, B., 29, 34 
Bowman, K., 42, 47 
Bozzetti, L. P., Jr., 9, 83, 95 
Bradt. C, 81, 96, 101, 107 
Brand, S. X., 82. 96 
Branda, L. A., 38, 47 
Braden, W„ 81, 91 
Braude, M. C. 36. 37. 38. 45, 47, 48, 49, 

52. 53, 59, 61, 68, 71, 74 
Breed, G., 88, 92 
Briant. R. H.. 30, 34 
Brill. X. Q., 12, 24, 25, 80, 91 
Brin. S. S.. 103, 108 
Brine. D. R., 31, 33, 76, 96 
Britton, R. S., 44, 46 
Brown, A., 7, 86, 91 
Brown, D. J., 117, 122 
Brown, J., 77, 91 

Bruce, P. D.. 62, 63, 66, 69, 70, 72 
Bruhn, P., 12, 86, 91 
Brunk, F., 116. 121 
Brunk, S. F., 62, 68, 85, 96 
Brunnemann, K. D., 38, 47 
Brvant. S. A., 100, 107 
Buckley. J. P., 41. 42, 46. 50 
Bueno, O. F. A., 65, 66, 70, 72 
Burns, M., 82, 96 

Burstein, S., 30, 32, 51, 58. 118, 120 
Butler, J. R., 85, 96, 117, 122 
Butler, R. C, 41, 49 



(123) 



124 



Cais, M., 30, 32 

Canafax, D. M., 45, 47 

Canter, A., 62, 68, 82, 96, 116, 121 

Cappell, H., 84, 91 

Carchman, R. A., 109, 115, 121 

Carder, B., 54, 57, 69, 70, 72, 73 

Carlin, A. S., 82, 84, 87, 91 

Carlini, E. A., 44, 48, 51, 52, 53. 54, 55, 56, 

57, 58, 59, 62, 65, 66, 67, 70, 71, 72, 

73, 76. 94, 114, 121 
Carvalho, F. V., 39, 49 
Cassidv, J., 7, 42, 46, 77, 91 
Castagnoli, N., Jr., 28, 32 
Castillo, J. D., 91 
Cavero, L., 41, 42, 46, 50 
Caveness, C, 80, 89, 90, 93 
Cely, W., 40, 44, 48, 50, 114, 121 
Chance, M. R. A., 55, 57 
Chao, F. C, 29, 33 
Chapman, L. F., 7, 59 
Chausow, A. M., 80, 91 
Chavez-Chase, M., 81, 97 
Chesher, G. B., 41, 44, 45, 46, 48, 52, 57, 

69, 70, 71, 72 
Chiang, C. Y., 99, 106 
Chin, L., 52, 57, 114, 120 
Chin, P., 41, 46 
Christ, W., 51, 52, 58 
Ohristensen, H. D., 81, 33, 76, 96 
Christie R. L., 7. 12, 24, 25, 80, 87, 91 
Clark, D. L., 55, 58 
Clark, S. C, 41, 46, 77, 82, 91, 95, 96 
Clayton, R. R., 3, 20, 23, 24, 26 
Clemens, J., 79, 95 
Clough, J. M., 31, 34 
Coggins, W. J., 27, 86, 88, 89, 91 
Cohen, M. J., 82, 88, 92 
Cohen, R., 17, 18, 25 
Cohen, S., 9, 79, 80, 88, 93, 95, 110, 120, 

121 
Cohn, R. A., 31, 32 
Colaiuta, V., 88, 92 
Collins, F. G., 41, 46 
Colin, R., 39, 46 
Comitas, L., 12, 22, 26, 86, 88, S9, 97, 110, 

122 
Congreve, G. R. S., 87, 90, 95 
Connor, T., 100, 106 
Consroe, P. F., 45, 46, 52, 55, 57, 58, 114, 

120 
Cooler, P., 15, 113, 120 
Cooper, C. W., 53, 57 
Coper, II., 44, 47, 52, 53, 58, 69, 72 
Corcoran, M. E., 62, 66, 71, 72 
Corvalho, F. V., 54, 59 
Cottrell, J. C, 38, 47 
Crabtree, R., 79, 95 
OraigmlU, A. L., 45, 47 
Craven, C, 41, 46 
Creasser, C, 117, 122 
Crowshaw, K., 43, 44, 47 
Culver, C. M., 86, 92 
Cunningham, I. C. M., 22, 25, 87, 92 
Cunningham, W. II., 22, 25, 87, 92 
Curtiss, F. R., 45, 47 



Cushman, M., 28, 32 
Cushman, P., 81, 92, 102, 106 
Cushman. R., 102, 106 
Cutler, M. G., 55, 57 
Cutting, M., 38, 47, 78, 92 

Daley, J. D., 39, 47 

Dalton, B., 81, 96, 102, 104, 107 

Dal ton, W. S., 76, 82, 92 

Dalzell, H. C, 28, 33, 34, 39. 50, 63, 68 

Dani, S., 30, 32 

Darley, C. F., 82, 85, 92, 98 

Davis, B. H., 78, 92, 93 

Davis, J. P., 114, 120 

Davis, K. H., 31, 33, 40, 49 

Davis, M., 99, 107 

Davis, R., 82, 92, 116, 120 

Davis, T. R. A., 61, 62, 66 

Davis, W. M., 44, 46, 47, 51, 53, 57, 63, 66 

deFaubert Maunder, M. J., 29, 32 

Deiderich, L. R., 28, 32 

DeJong, Y., 53, 55, 59 

Del Castillo, J., 39, 47 

DeLean, A., 77, 97 

deMello, D. N., 88, 97 

de Nie, L. C, 30, 33 

Derouaux, M., 41, 48 

DeSoize, B., 81, 97, 102, 103, 106, 107 

De Souza, M. R. C, 82, 92 

Devenyi, P., 87, 90, 95 

Dewey, W. L., 09, 70, 72, 73, 88, 92, 99, 

106, 107 
Dews, P. B., 61, 62, 66 
Dienel, B., 28, 33 
Dikstein, S., 114, 121 
DiMascio, A., 115, 121 
Dittrich, A., 82, 92 
Dolby, T. W., 43, 47 
Dollery, C. T., 30, 34 
Domino, E. F., 61, 63, 68, 69, 73, 82, 92, 

103, 106 
Doorenbos, N. J., 112, 122 
Dornbush, R. L., 82, 88, S9, 90, 92, 94 
Dorrance, D., 100, 106 
Dott, A. B., 83, 92 
Drew, W. G., 51, 52, 57, 58, 59, 61, 64, 

65, 66, 68, 80, 92, 119, 120 
Dubas, T. C, 116, 122 
Dubinsky, B., 54, 55, 56, 58, 61, 65, 67, 

70, 72 
Dubowski, K. M., 77, 79, 97 
Ducharme, J. R., 39, 46 
Dunn, D, 116, 120 
Dunn, M., 82, 92 
Dustman, R. E., 69. 74 
Dykstra, L., 62,63, 66 

Edery, H., 112, 121 
Edwards, G., 75, 92 
Ehrlich, D., 82, 92 
Ehrnebo, M., 77, 98 
Eisenman, R., 22, 25, 87, 93 
Elinson, J., 18, 25 
Ellingboe, J., 79, 95 
Ellingslad, V. S., 83, 92 



125 



Ellington. A. F., 99, 107 

Elsmore. T. F., 54, 56, 58, 59, 62, 63, 

66, 70. 72 
Ely. D. L., 55, 58 
El-Yousef, M. K., 76, 93 
Emboden, W. A. V., 110, 120 
Englert, L. F.. 42, 47 
English. W. D.. 22, 25, 87, 92 
Ercan. Z. S., 43, 48 

Ertel, R. S.. 42, 50 
Esber. H. J., 39, 47 
Estevey. V. S., 29, 33 
Evans, M. A., 76, 90, 92, 93 
Evenson, R. C, 86, 91 

Fariello, R. G., 41, 48 

Faust, R., 23, 25, 26 

Feeney. D. M., 114, 121 

Fehr, K. A., 64, 68 

Fehr, K. O., 31, 32 

Feinberg, I., 80, 89, 90, 93 

Fernandes, M., 44, 47, 53, 58, 69, 72 

Fernandes, N. S., 55, 59 

Ferraro, D. P., 53, 54, 58, 62, 63, 64, 66, 

67, 69, 70, 72, 73 
Fetterolf, D. J., 53, 54, 58, 70, 73 
Filipovic, N., 29, 32, 77, 94 
Fink, M., 80, 88. 89, 90, 93 
Fisher, G., 80, 93 

Fisher, S., 62, 68. 84, 96 

Fitzgerald, M., 78, 98, 113, 122 

Fleisehman, R. W., 37, 38, 49 

Fletcher, G., 54, 58, 62, 66 

Flom, M. C, 81, 93, 113, 120 

Foltz, R. L., 28, 32 

Forbes, W. B., 53, 58 

Forinan, E. S., 29, 34, 77, 97 

Fornev, R. B., 76, 82, 92, 93 

Forest, I. S., 29, 32, 33 

Fournier. E., 99, 106 

Fraley, S., 62, 68 

Frank. I. M., 8. 11, 15, 78, 88, 90, 93, 97, 

112, 113, 121, 122 
Frank. Ira R., 15, 112, 121 
Frankenheim, J. M., 62, 63, 67, 69, 70, 73 
Freedman, D., 88, 97, 114, 120 
Freemon, F. R., 76. 93, 115, 120 
Frei, E., 15, 118, 122 
Fried, P. A.. 52. 58, 69, 72 
Friedman, E., 45, 47, 52, 58, 71, 73, 118, 

121 
Friedman, J. G.. 79, 93 
Friedman. M. A., 99. 106 
Fry. D., 29, 33, 77, 95 
Fujiwara, M., 43, 50 

Gaensler, E., 78, 98, 113, 122 
Galbreath, C, 100, 106 
Gaoni, Y., 112, 121 
Garcia, J. F., 39, 48 
Gardner, L. I., 100, 107 
Garrett, E. R., 28, 29, 32 
Gartner, J., 117, 122 
Gastaut, H., 8, 80, 97, 116, 122 
Geber, W. F., 99, 106 



Gerber, M. L., 84, 94 
Gershon, H., 30, 32 
Gershon, S., 45, 47, 52, 58, 71, 73, 82, 88, 

91, 118, 121 
Ghosh, J. J., 44, 49, 51, 59 
Gibbins, R, J., 87, 90, 95 
Gibbs. J. W.. 41, 42, 50 
Gill, E. W., 31, 33 
Gillespie, H. K., 75. 76, 94 
Gilmour, D. G., 100, 106 
Glick, S. D., 53, 54, 58 
Gluck. J. P., 54, 58, 63, 64, 66, 67, 68, 

70,73 
Goldberg, M. E., 54, 55, 58, 61, 65, 67, 

70,72 
Goldstein, R., 22, 25, 87, 93 
Gonzalez, S. C., 54, 57, 62, 67 
Goode, E., 88, 93 
Goodenough, S., 38, 47, 78, 92 
Goodman, M. M., 28, 33 
Goodwin, D. W., 116, 121 
Goodwin, F. K., 85, 91, 116, 121 
Gori. G. B., 38, 47 
Gottschalk, L. A., 7, 77, 96 
Gough, A. L., 52, 58 
Gould, I. A., 113, 122 
Gould, L. C., 88, 93 
Graham, J. D. P., 42, 43, 47, 78, 81, 92, 

93, 96, 102, 104, 107 
Goyos, A. C, 54, 57 
Graziani, Y., 79, 97 
Green, D. E., 29, 31, 32, 33, 76, 94 
Green, K., 42, 47, 113, 120 
Green, M. L., 85, 96 
Greenberg, I., 11, 12, 62, 68, 87, 88, 90, 95 
Greene, C., 77, 91 
Greene, M. L.. 76, 93, 96 
Gregg, J. M., 15, 113, 117, 120 
Grieco, M., 81. 92, 102, 106 
Grilly, D. M„ 69, 70, 72, 73 
Grinspoon, L., Ill, 112, 121 
Grisham, M. G., 69, 72 
Gross, S. J., 29, 32 
Grossman, J. C., 22, 25, 87, 93 
Grungfeld. Y., 112, 121 
Gunderson, E. K. E„ 87, 93 
Gunn, C. G., 77, 79, 97 
Gupta, L., 61, 68, 69, 74 
Gupta, S., 81. 92, 102, 106 
Gustafsson, B., 29, 34, 75, 95, 112, 120 

Hadley, K. W., 28, 29, 34 

Hager, M., 80, 93 

Hahn, P., 11, 88, 90, 93 

Halaris, A., 88, 97 

Halikas, J. A., 11, 25, 84, 85, 86, 93 

Hall, M., 58 

Halpern, L. M., 84, 91 

Handrick, G. R., 28, 33, 39, 50 

Haq, M., 28, 32 

Harakal, J. J., 43, 49 

Harbison, R. D., 99. 107 

Harclerode, J., 41, 49 

Hardman, H. F., 41, 46, 47, 77, 93 

Hardy, X., 99, 106 



126 



Harmon, J., 38. 47, 79, 93 

Harpalani, S. P., 29, 34 

Harper, C. E., 15. 113. 122 

Harris, L. S., 53, 57, 63, 66. 67, 69, 70. 72. 

73, 88, 92, 99, 106, 107, 109, 115, 121 
Harris, R. T., 70, 71, 73 
Hays. J. R.. 21, 25 
Heath, R. G., 12, 80, 93 
Heerma, W., 20, 22. 32. 33 
Hefner. M. A., 61. 65, 67, 68 
Hembree, W., 9. 98 
Heneen. W.. 81. 96, 101. 107 
Henrich, R. T„ 101, 107 
Henriksson, B., 53, 58, 59, 64, 65, 67, 70, 

74 
Henry, J., 28, 34, 55, 58 
Henry, J. T., 28, 34, 76, 98 
Henry, T. J., 22, 25 
Hepler, R. S., 15, 82, 112, 121 
Herha, J., 100, 106 
Herndon, G. B., 63, 66 
Heyman, I. A., 38, 48, 49 
Hicks, R. C, 87, 90, 95 
Hill, R.. 44, 47, 51, 52, 53, 58, 69, 72 
Hill, S. Y., 116, 121 
Hill, T. W., 79, 93 
Hine, B., 45, 47, 71, 73, 118, 121 
Hirschhorn. I. D., 65, 67, 71, 73 
Ho, B. T., 29, 33, 42, 43, 46, 47 
Hoffmann, D.. 38, 47 
Holley, J. H„ 29, 34 
Hollister, L. E., 29, 31, 32, 53, 58, 75, 76, 

79, 93, 94, 96, 101, 107 
Holmstedt, B., 29, 34, 112, 120 
Hosko, M. J., 77, 93 
Houser, V. P., 61, 62, 67, 69, 73 
Howes, J., 39, 43, 47, 49, 50, 63, 68 
Hsu, J., 102, 103, 106, 107 
Huber, G., 78, 92 
Hulberr, S., 82, 83, 96 
Hunt, C. A., 29, 32 
Hunt, D. G.. 23, 25 
Huthsing, K., 53, 54, 58 

Tnui, N., 101, 107 
Irwin, J. E., 44, 48 
Izquierdo, I., 61, 62 

Jackson, D. M., 41, 44, 45, 46, 48, 52, 57, 

59, 69, 70, 71, 72 
Jakubovic, A., 31, 32 
Jandhyala, B. S.. 41, 46 
.Tanicki, B. W., 103, 108 
Janiger, O., 100, 106 
.Tanowsky, D. S., 9, 83, 95 
Jarbe, T. U. C, 53, 58, 59, 64, 05, 67, 70. 

74 
Jarosz, O. J.. 55, 58 
Jarrik, L. F.. km. 107 
.lessor, It.. 23, 'J.*i 
Johansson, J. O., 64. 65, 67 
Johnson. R. J.. 99, 106 
Johnston, L. D., 19. 25 
Johnstone, R. E„ 76, 77, 78 



Jones. B. C, 45, 46, 52, 55, 57, 58, 114, 

120 
Jones, G., 51, 58, 77, 98 
Jones, R. T., 11, 77, 80, 81, 85, 88, 89, 90, 

91, 93, 94, 103, 106, 113, 120 
Josephson, E., 18, 19, 25 
Josephy, Y., 30, 32 
Just, W. W„ 29, 32, 77, 94 

Kabelik, J., Ill, 121 

Kalant, H., 30, 31, 32, 33, 64, 68, 75, 94 

Kalant, O. J., 75, 94 

Kaniel, A. A., 79, 98 

Kandel, D., 23, 25, 26 

Kanter, S. L., 29, 31, 32, 76, 94, 96, 101, 

107 
Karler, R., 40, 41, 46, 48, 50, 114, 121 
Karniol, I. G., 44, 48, 49, 51, 52, 53, 54, 

55, 59. 62, 67, 76, 82, 91, 92, 94 
Karr, G., 77, 82. 91, 95, 96 
Kasinski, N., 76, 94 
Kaymakcalan, S., 40, 41, 43, 48, 62, 67, 

69, 73, 116, 121 
Keeler, M. H., 85, 94 
Kensler, C. J., 61, 62, 66 
Kephalas, T. A., 79, 96 
Khan, M. A., 71, 73 
Khanna, J. M.. 30, 33 
Khurana, R., 102, 106 
Kilbey, M. M., 53, 55, 58 
Kim, K., 42, 47, 113, 120 
Kimball, A. P., 43. 46 
Kimmel, G. L.. 31, 33 
Kinchi, If., 103, 104, 107 
King, F. W., 86. 92 
King, L. J., 29, 31, 34, 77, 97 
King, M. R., 87. 94 
King, S.. 100. 107 
Kinzer. G. W., 28, 32 
Kirk, T.. 85, 96 
Kleber, II. U.. 88, 93 
Klein. V., 77, 78, 95 
Kleinsmith, L. J., 43, 47 
Klonoff, H., 80. 82, 83, 94 
Kluwe, S., 44, 47 
Knapp, J. E., 28, 33 
Knobloch, L. C. 43, 45, 49, 115, 122 
Knox. G. V., 64. 08 
Knudten, R. D., 88, 94 
Koff, W., 79, 80. 94 
Kokka. N., 39, 48 
Kokkevi, A.. 88, 89. 90, 94 
Kolanskv, H.,86, 95 
Kolb. 1)., 87, 93 
Kolodnor. R. M., 39, 48, 79, 95 
Kolodny, R. C., 9, 39, 48, 79, 80, 95, 110, 

121 
Kosersky, D. S.. 63, 67, 69, 73 
Kotin, J.. 116, 121 
Kramer, J., 39, 48 
Krantz, J. C, 52,58 
Krimmer, B. C, B4, 65, 66 
Krng, S. E. f 22, 25 
Kubena, R. K., 64, (56, 67 
Kuchar, F., 84, 91 



127 



Kuehnle, J. C. 11, 12, 79, 87, 88, 90, 95 

Kulp, R. A.. 76, 77. 78, 94, 93, 117, 121 

Kumar, S., 101, 106 

Kunwar, K. B., 101, 106 

Kunvsz, T. J., 100, 108 

Kuo, E. H., 39, 47 

Kupfer, D., 51, 58 

Kuppers, F. J. E. M., 28, 32, 33 

LaGuardia, R., 38, 47, 48, 92 

Lahiri, P. K., 77, 93 

Laird, H., II, 41, 46, 114. 120 

Lander. X., 114, 122 

Lau. R. J., 103, 106 

Laurenceau, J. L.. 77. 97 

Laverty, W., 7. 77. 96 

Lawrence. D. K.. 31, 33 

Leander. K., 29, 34, 75. 95. 112, 120 

LeBlane, A. E., 64, 68 

Leboeuf, G.. 39. 46 

Lee, Y. E., 15. 113. 122 

Lefkowitz, S. S., 99. 106 

Legator. M. S., 100. 106 

Lehrer. G. M., 71, 73 

Leite. J. R.. 71. 73 

Lele. K. P.. 100. 106 

Lemberger. L.. 75. 76. 77. 79. 81, 82, 92, 

93, 95, 96. 102. 104, 107 
Lerner, C. B.. 103. 106 
Lessin, P., 9, 10. 79. 88. 90, 93, 95, 97, 103, 

104. 107. 110, 121 
Letarte, J., 39. 46 
Leuchtenberger. C. 3S, 50. 99, 101. 106, 

107 
Leuchtenberger, R., 38, 50, 99, 101, 106, 

107 
Levander, S., 75, 95 
Levin. E.. 51, 58. 118. 120 
Levy. J. A.. 99. 107 
Levy. S., 30, 33 
Lewis, E. G., 69. 74 
Lewis. M. J., 42, 43, 47 
Li. D. M. F., 42, 43, 47 
Liakos. A., 86, 88, 90. 97 
Lief, P. L.. 76. 77. 78, 94. 117. 121 
Lindgren, J. E., 30, 34, 75, 95, 112, 120 
Ling, G.. 82, 98 
Lipton, M. A.. 31. 33 
Liu. R. K., 41, 48 
Livine. A.. 79, 97 
Lodge. J. W., 15. 113, 121 
Loeffler. K. O., 29, 32, 33 
Loev, B.. 28, 33 
Lokhandwala, M. F., 41, 46 
Lomax, P., 40, 49 
Loskofa. W. J., 40, 49 
Lott, G. C. 57 
letter. H. L.. 28. 33 
Lousberg. R. J. J. Ch., 28, 32, 33 
Low. M. P.. 80, 94 
Lubas, T. C. 116, 122 
Luthra, Y. K., 37, 43. 48 
Lutz. M. P.. 61, 63. 68, 69, 73 



McCallum, X. K., 30, 33, 77, 95 

McCarthy, K. D., 42, 50 

McCaughron. J.. 62, 66 

McDonough, J. H., 56, 59 

McFarling, L. H., 83, 92 

McGeer, P. L., 31, 32 

McGlothin, W. H., 22, 26, 82, 83, 96 

McGuire, J. S., 88, 95 

McKenna, G. J., 85, 96 

McLendon, D., 70, 71, 73 

McMahon, R.. 75, 77, 95 

M' Meens, R. R., Ill, 121 

McMillan, 1). E., 40, 62, 63, 66, 67, 69, 70, 

72, 73 
McXair, D. M., 62, 68, 84, 96 
McXaniara, M. C, 114, 120 
McNeil, J. H., 70, 73 

Maage. X., 12. 86, 91 

MacConaill, M., 82, 98 

MacCannell, K. L., 77, 82, 91, 95, 96 

Mackintosh, J. H., 55, 57 

Macpherson, A. S., 29, 34 

Maker. H. S., 71, 73 

Maleson, F., 88, 96 

Malit, L. A., 77, 78, 95 

Malor, R. M., 45, 46, 48, 52, 57, 59, 69, 

70, 72 
Man, D. P., 114, 120 
Manaster, G. J., 87, 94 
Manheimer, D. I., 24, 26 
Manning, F. J., 56, 59, 61, 63, 66, 67, 69, 

70, 73 
Mantilla-Plata, B., 99, 107 
March, J., 80, 89, 90, 93 
Marks, V., 29, 31, 33, 34, 95, 97 
Marquis. Y., 77, 97 
Marriott, R. G., 69. 73 
Marshman, J., 87, 90, 95 
Martin, B. R., 88, 92 
Martin, P. A., 99, 100, 107 
Martz, R. C, 76, 82, 92, 93, 117, 122 
Masoud, A., 112, 122 
Masters, W. H., 9, 39, 48, 79, 80, 95, 110, 

121 
Masur, J.. 54. 57 
Matsuyama, S. S.. 101, 107 
Mattison, J. B., Ill, 121 
Maximillian. C., 100, 106 
Meacham, M. P., 9, 83, 95 
Meade, A. C. 88, 95 
Mechoulam, R., 30, 32, 33, 43, 46, 51, 59, 

112, 114. 118. 120, 121 
Megargee, E. I., 88, 95 
Meldrum, B. S., 41, 48 
Mellinger, G. D., 24. 26 
Mello, X.. 11. 12, 87. 88, 90, 95 
Mellors. A.. 44. 46, 48 
Mendelson. J. PL, 11. 12, 78, 79, 87, 8S, 

SO. 90, 95 
Meyer, R. E., 11, 78, 84, 85, 86, 88, 89, 90, 

95 
Meyers, A. L., 88, 96 
Michael. C. M., 79, 96 
Micbelson. A. E.. 24, 26, 88, 96 



128 



Mickey, M. R., 104, 107 

Miczek, K. A., 54, 55, 56, 59 

Mikus, P., 78, 98 

Miles, C. G., 87, 90, 95 

Miller, L. L„ 51. 52, 57, 58, 59, 61, 64, 65, 

66, 68,75, 80, 92, 95, 119, 120 
Miller, R. C, 81, 96, 101, 107 
Milloy, S., 53, 54, 58 
Milstein, M., 101, 107 
Milstein, S. L., 77, 82, 91, 95, 96, 116, 121 
Miras, C. J., 79, 96 
Mirin, S. M., 85, 96 
Mitchell, R. I., 28, 32 
Mobarak, Z., 29, 33 
Modiano, A., 30, 32 
Mole, M. L., 28, 29, 34 
Morrissey, W., 78, 98 
Moore, E., 85, 94 
Moore, F., 29, 31, 32, 76, 94 
Moore, J. W., 58 
Moore, W. T., 86, 95 
Moreau de Tours, J. J., Ill, 121 
Morishima, A., 81, 96, 97, 100, 101, 102, 

106, 107 
Morrow, C. W., 64, 67 
Mosher, R., 82, 98 
Moskowitz, Z. H., 82, 83, 96, 97 
Muchov, D., 70, 73 
Mullins, C. X, 24, 26, 88, 96 
Munson, A. E., 99, 106, 107, 109, 115, 121 

Nace, E. P., 88, 96 

Xa ditch. M. P.. 85. 96 

Xagel, M. D., 99, 107 

Xahas, G. G., 81, 96, 97, 99, 100, 101, 

102, 103, 106, 107 
Xail, R. L., 87, 93 
Xash, J. B., 31, 32 
Xasselo, A. G., 61. 67 
Xaiiboff, B. D., 82, 92 
Xaquet, R., 41, 48 
Xazar, B. L.. 41, 49 
Needle, M., 81, 97 
Xeu, C, 115, 121 
Xeu, R. L.. 100, 107 
Newman, L. M., 61, 63, 68, 69, 73 
Xichols, W. W., 81, 96, 101, 107 
Xieman, G. W., 52, 58 
Nilsson, I. M., 30, 33, 34, 112, 120 
Xordqyist, H., 30, 33, 34 
Xoyes, R., 62. 68, 82, 85, 96, 110. 121 
Nunes, J. F., 39, 49, 54, 59 

Obo, G., 100, 106 

O'Donnell. J. A, 3, 20, 23, 24, 26 

Ohlsson, A., 75, 95 

Olivetti, C, 53. 58 

Ollov, J. E., 52, 58 

Olson, D. M., 40, 41, 44. 46, 50 

Olsen, J. L., 15, 113, 121 

Olson, J.. 54. 57. 60, 70. 72. 73 

Opelz, G., 103, 104, 107 

Opinion Research Corporation, 17, 18, 26 

Orcutt, J. D.. S3. 06 

OrndofT. R. K., 07 



Osgood, P., 43, 47, 49 

O'Shaughnessy, W. B., Ill, 112 

Overall, J. E., 84, 94 

Pace, H. B., 51, 53, 57, 99, 107 

Palmero Neto, J., 39, 49, 54, 59 

Papadakis, D. P., 79, 96 

Parker, O. S., 112, 122 

Parker, J. M., 28, 33, 116, 122 

Pars, H. G., 63, 68 

Patel, A. R., 28, 32 

Paton, W. D. M., 45, 49, 117, 122 

Payer, L., 82, 96 

Payne, R. J., 82, 96 

Pearl, J. H., 82, 92 

Peek, L„ 85, 96 

Peraita-Adrados, M. R., 7, 79, 97 

Perez-Reyes, M., 31, 33, 40, 49, 88, 96, 98, 

115, 122 
Perkins, J., 29, 34 
Persaud, T. V. X., 99, 107 
Pertwee, R. G., 31, 33, 39, 49, 51, 58 
Petersen, A. C., 40, 49, 115, 122 
Petersen, B. H., 81, 96, 104, 107 
Petersen, D. M., 23, 26 
Petrus, R., 112, 121 
Pfeferman, A., 76, 94 
Piall, E. M., 31, 34 
Picchioni, A. L., 114, 120 
Pickens, R., 70, 73 
Pillard, R. C., 62, 68, 75, 84, 96 
Piper, J. M., 31, 33 
Pirch, J. H., 31, 32 
Pliner, P., 84, 91 

Plotnikoff, X. P., 40, 49, 115, 122 
Poddar, M. K., 51, 59 
Post, R. D., 84, 87, 91 
Post, R. M., 116, 121 
Powell, B. J., 116, 121 
Powers, H. O., 100, 107 
Prakash, R., 7, 77, 96 
Prendergast, T. J., 23, 26 
Prima vera, L. H., 97 
Proctor, R. C., 112, 122 
Pryor, G. T., 52, 53, 59, 61, 68, 76, 96 
Puil, E. A., 41, 48 

Quimby, M. W., 112, 122 

Rachelefeky, G. S., 10, 104, 107 

Radcliffe, S., 78, 92 

Rafaelsen, L., 75, 91 

Rafaelsen, O. J., 75, 91 

Ramsey, H. H. 114, 120 

Rappeport. M., 17, 18, 25 

Rav, A., 118, 120 

Razdan, R. K., 28. 33, 34, 39, 50, 63, 68 

Reavan. G. M., 79, 94 

Regan, J. D., 102, 106 

Rogelson, W., 85, 96, 117, 122 

Reinking, J., 41, 46, 114, 120 

Renault, P. F., 76, 88, 91, 97 

Rennick, P., 82, 92 

Revnolds. .T. R., Ill, 122 

Rich. E., 82, 08 

Rickles, W. H., 82, 88, 92 



129 



Rimmer, J. D., 22, 25 

Ritter, U., 101, 107 

Robbins, E. S., 100, 106 

Roberts, J., 29, 34 

Robichaud, R. C, 54, 55, 56, 5S, 61, 65, 

67, 68, 70, 72 
Robins, L. N., 23, 26 
Rodda, B. E., 76, 82, 92, 93 
Room, R. G. W., 3, 20, 23, 24, 26 
Rosenberg, C. M., 118, 122 
Rosenberg, E., 99, 106 
Rosenblatt, J. E., 76, 93 
Rosencrans, J. A., 65, 67, 71, 73 
Rosenfeld, J., 29, 34, 38, 47 
Rosenkrantz, H., 36, 37, 38, 39, 43, 47, 

48, 49, 53, 59, 71, 74 
Rosenthal, D., 29, 34 
Rossi, A. M., 11, 78, 88, 89, 90, 95 
Roth, R. I., 41, 49 
Roth, W. T., 82, 92 
Rothberg, J. M., 88, 96 
Rowe, H., 79, 95 
Roy, P., 77, 97 
Rubenstein, K., 30, 33 
Rubin, V., 12, 22, 26, 86, SS, S9, 97, 110, 

122 
Rubottom, G. M., 39, 47, 91 

Salemink, C. A., 28, 32, 33 

Sallan, S. E., 15, 118, 122 

Salzrnan, C, 88, 97 

Sarnie, J., 28, 32 

Sampaio, M. R, P., 55, 59 

Sandberg, F., 30, 34, 112, 120 

Santos, M., 55, 59 

Saper, C. B., 80, 91 

Sarkar, C, 44, 49 

Sassenrath, E. N., 7, 59 

Saunders, D. R., 76, 93 

Savary, P., 77, 97 

Schabarek, A., 44, 47, 52, 53, 58, 69, 72 

Sehaefer, C. F„ 77, 79, 97 

Schaeppi, U., 37, 49, 71, 74 

Schiff, P. L„ Jr., 28, 33 

Schorr, M„ 9, 83, 95 

Schoolar, J. C, 29, 33 

Schramm, L. C, 99, 106 

Schrayer, D„ 17, 18, 25 

Schulz, J., 85, 96 

Schurr, A„ 79, 97 

Schuster, C. R., 76, 88, 91, 97 

Schuster, R. E., 29, 32 

Schwartz, I. W„ 99, 107 

Schwartzfarb, L., 81, 97 

Schwin, R., 116, 121 

Seaton, A., 78, 92, 93 

Segelman, A. B., 43, 49, 81, 97 

Segelman, F. P., 43. 49. 81, 97 

Shader. R. I., 88. 97 

Shani. A., 112, 121 

Shapiro, B. J„ 8, 15, 78, 97, 113, 114, 121 

122 
Sharma, S., 82, 97 
Sharma, S. C, 29, 34 
Shattuck, D. X., 39, 49 



Shea, R., 82, 96 

Sheffer, N., 79, 97 

Shehorn, J„ 82, 91 

Shelton, F. S., 30, 34 

Sheehan, J. C, 63, 68 

Shirakawa, I„ 7G, 94 

Siemens, A. J.. 30, 31, 33 

Sikic, B„ 88, 97 

Silverstein, M. J., 81, 97, 103, 104, 107 

Simmons, G., 78, 92 

Simmons, J., 31, 33 

Simon, M. G., 97 

Simon, W. E.. 87, 97 

Single, E„ 23. 26 

Sivil, S., 41, 48 

Sjoden, P. O., 53, 59, 70, 74 

Slatkin. D. J., 28, 33 

Slat in, G. T., 3, 20, 23, 24, 26 

Small, E. W., 117, 120 

Smart, R. G„ 82, 83, 97 

Smith, G. E., 23, 26 

Smith, H. J., 55, 58 

Smith, T. 0., 77. 78, 84, 95, 117, 121, 122 

Snyder, E. W., 69, 74 

Snyder, E. H., 43, 46, 118, 120 

Soares, J. R.. 29, 32 

Sofia, R. D., 43, 45, 49, 53, 54, 59, 70, 74 

100, 106, 115, 122 
Sohn, S. S., 38, 47 
Sollidav, N. H., 113, 122 
Solomon, J., 39, 49 
Solomon. T. A., 42, 50 
Somers. R. H., 24, 26 
Sprague. R. A., 37, 49 
Srinivison, P. R., 103, 107 
Stadnicki, S. W., 37, 49, 71, 74 
Steckler, A„ 80, 93 
Steele, R. A.. 114, 120 
Stefanis, C., 86, 88, 90, 97 
Stembal, B. L., 28, 33 
Stenchever, M. A., 100, 108 
Stickgold, A., 86, 91 
Stiehm, E. R., 103, 104, 107 
Stillman, R. C„ 81, 91 
Stoeckel, M., 100, 106 
Stoelting, R. K„ 117, 122 
Stormer, G. A., 45, 46, 52, 57 
Stromberg, L.. 28, 29, 34 
Struckman, D. L., 83, 92 
Suchman, E.. 23. 26 

Suciu-Foca. X., 81, 97, 100, 102, 103, 107 
Sulkowski, A., 82, 98 
Swanson, G. D., 79, 98 
Szara, S., 11, 88, 90, 93 

Tait, R. M., 31, 32 

Takahashi, R. X., 44, 49, 52, 53, 54, 55, 

59 
Tashkin, D. P., 8, 15, 78, 97, 113, 114. 

121, 122 
Tassinari, C. A.. 8, 80. 97, 116, 122 
Tayal, G., 61. 68, 69, 74 
Tavlor. D„ 42. 47 
Teale. D., 29. 33. 77, 95 
Teale. J. D.. 29, 31, 34. 77, 97 
Tec. X., 88, 97 



130 



Temple. D. M., 117, 122 

Ten Hani, M., 40, 49, 53, 55, 59 

Teplitz, R. L., 100, 106 

Terlouw, J. K., 28. 32. 33 

Tewari, S. X.. 29, 34 

Thoden, J. S., 82. 98 

Thomas. C. W., 23. 26 

Thompson, G. R., 38. 49 

Thompson, L. J.. 112, 122 

Thompson, P., 82, 98 

Thompson, T., 70, 73 

Thorburn, M. J., 106, 107 

Timmons, G., 38, 47 

Timmons, M. C. 31. 33, 40, 49, 88, 96 

Tinklenberg, J. R., 82, 85, 92, 98 

Tobisson, B., 75, 95 

Toro, G., 9, 39, 48, 79. 80. 95, 110. 121 

Torrello, M., 45, 47, 71, 73, 118, 121 

Truit, E. B., Jr., 28, 32, 45, 49 

Tsau, J.. 28. 32 

Tubergen, D. G., 103. 106 

Turk. R. F., 70, 72. 73 

Turkanis, S. A., 40. 41, 44, 46, 48, 50, 114, 

121 
Turker, M. X., 40, 48, 62, 67, 69, 73, 116, 

121 
Turker. R. K., 40, 43, 48, 62, 67, 69, 73, 

116, 121 
Turner. C. E, 28, 29, 33, 34, 76, 98, 112, 

122 
Tylden, E.. 85, 98 

Ueki, S., 43, 50 

Uliss, D. B., 28, 34, 39, 50 

Uyeno, E. T., 52, 55, 59, 64, 68, 100, 108 

Yaehon, L., 82, 98, 113, 122 
Van der Kolk, B. A.. 88, 97 
Vanlloeven, H., 28, 33 
van Xoordwijk, J., 55, 59 
Varanelli, C, 30,32, 118, 120 
Ventura, I). F.. 82, 92 
Vitola.B. M., 24,26, 88, 96 
Vogel, W. II, 38. 47 



Vollmer, R. R., 42, 50 
Voss, H. L., 3, 20, 23, 24, 26 

Wagner, D, 76, 96 

Wagner, H. R, 114, 120 

Wagner, M. J.. 62. 68 

Walker. J. M.. 80. 89. 90. 93 

Wall, M. E., 29, 31, 33, 34, 40, 49, 76, 88, 

96, 98 
Warren, M., 7, 77, 96 
Waters, W.. 70, 71. 73 
Watson, A.. 38, 47, 78, 92 
Weber, E., 100, 106 
Weiss, G., 114. 120 
Welch, B. L., 52, 58 
Werner, G., 29. 32. 77. 94 
White, S. C, 103, 108 
Widman, M, 30. 31, 34, 77, 98 
Wiersema, V., 99, 106 
Wikler, A.. 64, 68 
Williams, J., 31, 32 
Winburn. M. G.. 21, 25 
Wingtield. M., 115, 122 
Witsehi. H. P., 30, 34 
Wong. S. L. R, 29, 32 
Worning, X.. 51. 52, 58 
Wrigley, F. W., 112, 122 
Wyatt, R. J.. 81, 91 
Wynder, E. L, 38, 47 

Yagen, B., 30, 33 
Yagiela, J. A., 41. 42, 50 
Yankelovich. D., 20, 26 
Yoshimura, H., 43, 50 
Younglai, E. V., 38, 47 

Zagury, D, 99, 107 
Zaki. X.. 29, 33 
Zamir-Ul, R., 28, 32 
Zaugg, H. E., 40, 49, 115, 122 
Zimmer, D., 82, 92 
Zinberg, X. E.. 15. 118, 122 
Zinggraff, M. T, 23, 26 
Zitco, B. A., 63, 68 



SUBJECT INDEX 



abstinence syndrome, 70-71, 89 

(see also withdrawal syndrome) 

academic performance, 12, 86, 87 

acetylcholine, 43 

activity and exploration, 52, 53 

acute brain syndrome (toxic delirium ', 
86 

acute effects, 7-8, 75, 88 

acute panic anxiety reaction. 11, 85 

adolescent use, 3-5. 17, 21 

adult use, 3-5, 17, 20-24 

aerosolized delta-9-tetrahydrocannali- 
nol (THC), 113, 114 

aggressive behavior, 7, 39, 54-56, 88 

(see also competitive aggression, 
human aggression, isolation-induced 
aggression, predatory aggression 
and stress-induced aggression) 
olism, treatment of, 13. 109, 111, 
US 

amotivational syndrome. 11, 86, 87, 90, 
110 

analgesic effect, 14. 40, 44, 69, 82, 109, 
110, 111, 112, 116 

agina, 7, 42, 77 

anticonvulsant effects. 14. 27. 36, 39-41, 
43^4, 109, 111, 114, 115 

antidepressant effects, 14, 109, 112, 115, 
116 

antiemetic effect, 15, 109. 112, 118 

antimuscarinic effects, 77. 114 

antinauseant effect, 112. 118 

antitumor agent, 105. 109, 115 

assay techniques. 28-30, 31, 75, 112 

(see also chromatography, free rad- 
ical immunoassay, gas chromatog- 
raphy, gas-liquid chromatography, 
high pressure liquid chromatogra- 
phy and thin-layer chromatogra- 
phy) 

asthma, treatment of, 15, 78, 109, 111, 
113 
(see also bronchodilation) 

auditory effects, 8, 82 

aversive control, 61-62 

avoidance learning, 61 

bait shyness, 62 

benzopyrans, 40. 109. 112 

beta-adrenergic, 77. 78. 79 

blacks, use of marihuana, 21 

bradycardia, 42 

bronchodilation, 8, 110, 112, 113, 114 

cannabiehromene (CBC or CBCH), 28, 
36, 36, 37, 53, 62. 102 



Cannabicyclol, 102 

cannabidiol (CBD), 5. 28. 29, 31. 35. 30. 
37, 40, 31, 44, 51-55, 62, 63, 64, 69, 
71. 76, 101, 102, 114, 118, 119 

cannabigerol (CBG), 62 

cannabinoid interactions with non- 
cannabinoids, 35. 45, 76 

cannabinoid interacrions with 

eannabinoids, 35. 44-45. 51-53. 76 

eannabinol (CBN), 5, 27, 29, 30, 31, 40. 
51-55, 64, 76. 101, 111 

cannabis resin, 30 

Cannabis satiua L.. 28, 110, 111 

cannabis ti vine, 28 

carcinogenicity. 38 

alar effects, 7-8. 36. 37. 41-42. 
76. 8< 

cell-mediated immune response. SI. 101, 
1<>4. 105 

central nervous system, accumulation 
of cannabinoids in. 36 

< entral nervous system, effect en. : 
39. 40, 41. 41'. 80, 81 

chemistry of marihuana, 27-29. 75 

chromatography, 28-30, 76 (see also 
assay techniques, gas chromatog- 
raphy, gas-liquid chromatography, 
higli pressure liquid chromatog 
raphy, thin-layer chromatography I 

chromospnes, effects on, 10, 13, 99, 101 

chronic animal effects. 69-71 

chronic human effects, 88, 90 

college student use. 4-5, 19-20 

Columbia University, 18 

competitive aggression. 55 

oon^ummatory behavior. 53-54 

contingent negative variation (CNV), 
so. 81 

correlates of marihuana use, 1, 17 

criminal behavior, 88 

cross-tolerance, 41, 61, 63, 69 

delta-8-tetrahydrocannabinol ( THC ) , 
28, 40. 41. 45. 51. 52, 53. 54, 62, 
63. 64, 65, 71, 99, 100, 101, 102, 103, 
113, 114 

delta-9-THC-ether, 61 

deoxyribonucleic acid (DXA), 10, 99, 
101, 102, 103 

dependence, 10-11. 71, 89 

detection, 6, 28-30 (see also assay tech- 
niques, chromatography, gas-liquid 
chromatography, high pressure 
liquid chromatography and thin- 
layer chromatography) 



(131) 



132 



diniethyleptylpyran (DMPH), 31, 40, 41, 

75, 77, 115 
discrimination learning, 64-65 
distribution in body, 30-31 
dopamine (DA), 119 
dose effects, 56 

driving performance, 5, 8-9, 82, 83 
Drug Abuse Council, 17, 18, 19 
drug abuse, treatment of, 109, 112, 118 
drug progression, 23, 88 

8-alpha, ll-dihydroxy-delta-9-THC, 28, 
40 

electrocardiogram (EKG),77 

electroencephalogram (EEG), 12, 37, 
41, 45, 80, 89 

ll-hydroxy-delta-8-THC, 65 

ll-hydroxy-delta-9-THC, 27, 31, 40, 42, 
75 

endocrine effects, 9, 38-39, 79, 80 

enzyme multiplied immunoassay test 
(EMIT), 6, 29 

epilepsy, 35, 109, 111, 114 (see also anti- 
convulsant effects) 

exploratory behavior, 52-53 

extent of use in U.S., 1, 3, 17-22 

fetal effects, 9, 99 

5-hydroxytryptamine (5-HT), 38, 42-45 
(see also serotonin) 

flying performance, 9, 83 

"flashbacks," 85, 86 

food intake effects, 53, 110 

free radical immunoassay, 30 

Gallup, 1, 20 

gamma-ammobutyric acid (GAI5A), 43, 

119 
gas chromatography, 76 
gas-liquid chromatography, 28, 29 
genetic effects, animal, 99, 100 
genetic effects, human, 100, 101 
glaucoma, 8, 15, 109 
gross behavior, marihuana effects on, 

51-52 
gynecomastia, 38-39, 79 

hashish, 6, 14, 21, 53, 65, 70, S6 

hashish oil, 6, 21 

hashish resin, 29, 53 

hashish smoke, 65 

hashish suspensions, 70 

high pressure liquide chromatography, 

29 
higli school student use, 1, 3, 17-20 
homogeneous enzyme immunoassay, 30 
hormonal effects, 35, 38, 39, 79, 80 
human aggression, 88 
hydroxylution, 31, 75, 70 
hypothermic activity, 40, 41, 42^43 

immune respone, antibody mediated, 10, 

101 
immune response, cell mediated, 9-10, 

101,102 



immunosuppressant, 99 

Indian Hemp Drugs Commission, 110 

initiation of use, factors influencing, 22- 

23 
intraocular effects, 15, 42, 81, 112, 113 
isolation-induced aggression, 55 

learned animal behavior, 
lethal dose, 36, 38, 119 

male use, 20-30 age group, 1, 20-21 

male vs. female, concentration in tis- 
sue, 31 

male vs. female, effects, 31 

male vs. female use, 1, 17-18 

marihuana extract, 37, 40—11, 81 

marihuana tar, 38 

Marihuana Tax Act of 1937, 111 

mass spectroscopy, 28, 76 

maze learning, 

mechanism of action, 8, 42-44, 75, 118, 
119 

memory, 8, 81, 85 

mental performance effects, SI 

metabolism, 8. 30, 31, 75, 76 

metabolites, 27, 30, 31, 75, 76 

method of administration, 30-31 

military influence, 23 

minority use, 17, 21 

morphine-abstinence syndrome, block- 
ade of, 36, 45 

National Commission on Marihuana and 
Drug Abuse, 17, 18 

National Institute on Drug Abuse 
(NIDA), 11,99, 112 

neurological effects, 80 

neurotoxicity, 36-37 

nonconformity, relationship to marihua- 
na use, 1, 3, 22-23 

norepinephrine (NE), 42-43, 119 

olivetol, 28, 118 
open-field behavior, 

paranoid reactions, 85 
parent influence, 23 
peer group influence, 1, 23, 84, S7 
peceptual alterations, 82, 83 
pharmacological effects, 31, 39-45 
parahexyl (Synhexyl), 53, 112 
preanesthetic, 109, 112, 116 
predatory aggression, 55-56 
predictors of use, 23 
prostaglandins, 43, 113, 118 
psychomotor performance, 7-8, 82 
psychopathology, 13, 14, 84-88 
psychotic reactions, 11, 85-86 
pulmonary effects, 7, 43-44, 78-79 

radioimmunoassay, 6, 28, 31, 76 
reinforcement schedules. 62-63 
reproductive aspects, 9, 79-80, 99. 101 
ribonucleic acid (UNA), 10, 37, 43, 102 
righting reflex, 52 



133 



San Mateo County Survey, 1, 19-21 
sedative-hypnotic properties 7-8, 112, 

115, 116 
self -administration of marihuana, 70-71 
sensory function, 82 
sexual behavior, 79-80, 110 
sexual functioning, 9, 79-80, 110 
6-oxo-cannadidiol-diacetate, 114 
sleep, 7, 39-40, 44, 52, 80, 115 
Southern U.S., use, 17 
SP-111, 42, 63 
spontaneous activity, 53 
stress-induced aggression, 54-55 
student use, 1, 3, 17-21 
subjective response, nonpharmacologic 

determinants, 75, 83-84 
sympathetic nervous system, 41-43 



therapeutic aspects, 4, 14-15, 35^36, 109, 
119. (see also alcoholism, treat- 
ment of; analgesic effect; anticon- 
vulsant effect; antidepressant ef- 
fect; antiemetic effect; antinau- 
seant effect : bronchodilation ; drug 
abuse, treatment of; intraocular 
effects ; preanesthetic ; sedative- 
hypnotic) 

thin-layer chromatography, 28-29, 76 

tolerance, 10-11, 14, 30, 31, 38-40, 52, 61, 
63, 65, 69-70, 88, 89-90, 114, 116 

toxicity, 13-14, 35-38, 39-40, 45 

unemployment, relationship to mari- 
huana use, 24 
unlearned animal behavior, 51-56 
use of marihuana, 1, 3, 17-24 



tachycardia, 7, 40-41, 

117 
teratogenesis, 99, 100 
testosterone, 9, 79 



i7, 114, llo, water intake effects, 53-54 
Western U.S., use, 1, 17 
whites, use of marihuana, 1, 3, 17 
withdrawal symptoms, 11, 70-71, 1 



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